SPECIALIZED CENTERS FOR THE PROTEIN STRUCTURE INITIATIVE

RELEASE DATE:  April 1, 2004
 
RFA Number: RFA-GM-05-002

EXPIRATION DATE:  October 16, 2004  

Department of Health and Human Services (DHHS)
 
PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
 (http://www.nih.gov)   

COMPONENTS OF PARTICIPATING ORGANIZATION:  
National Institute of General Medical Sciences (NIGMS) 
 (http://www.nigms.nih.gov)  
National Center for Research Resources (NCRR)
 (http://www.ncrr.nih.gov)  

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: 93.859, 93.389 
 
LETTER OF INTENT RECEIPT DATE:  September 10, 2004
APPLICATION RECEIPT DATE:  October 15, 2004   
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o  Purpose of this RFA
o  Research Objectives
o  Mechanism of Support
o  Funds Available
o  Eligible Institutions
o  Individuals Eligible to Become Principal Investigators
o  Special Requirements
o  Where to Send Inquiries
o  Letter of Intent
o  Submitting an Application
o  Supplementary Instructions
o  Peer Review Process
o  Review Criteria
o  Receipt and Review Schedule
o  Award Criteria
o  Required Federal Citations

PURPOSE OF THIS RFA 

The National Institute of General Medical Sciences (NIGMS) and the 
National Center for Research Resources (NCRR) encourage applications 
for cooperative agreements to support specialized structural genomics 
research centers for methodology and technology development and new 
ideas and approaches for protein production and structure determination 
for classes of challenging proteins.  These specialized centers will 
form one component of the Protein Structure Initiative (PSI) Research 
Network, the integrated second, or production, phase of the PSI (PSI-
2).  They will focus on challenging proteins that are not currently 
amenable to high throughput and therefore represent major bottlenecks 
of the structural genomics pipeline.  These classes of proteins 
include, but are not limited to, membrane proteins, small protein 
complexes, and proteins from human and other higher eukaryotes.  The 
specialized centers will also be required to produce and determine the 
structure of significant numbers of these proteins, especially in the 
later years of the project.  

RESEARCH OBJECTIVES

A. Background

With the completion of the sequencing of the genomes of human and other 
organisms, attention has focused on the functional characterization of 
large sets of proteins.  The availability of sequence data, 
computational analyses of protein sequence families, technological 
developments in x-ray crystallography and nuclear magnetic resonance 
(NMR) spectroscopy, and the growing impact of structural biology on 
biomedical research has led to an international effort to determine 
protein structures on a large scale and to the emerging field of 
structural genomics.  The NIGMS played a major role in the early 
planning for this field and in 1999 organized a national program, the 
Protein Structure Initiative (PSI).

The long-range goal of the PSI is to make the three-dimensional atomic 
level structures of most proteins easily obtainable from knowledge of 
their corresponding DNA sequences.  The PSI plans to accomplish this 
goal by the creation and distribution of a large collection of protein 
structures. Structural studies by X-ray crystallography and NMR in a 
high throughput mode of operation will achieve a systematic sampling of 
major protein families.  These experimentally determined structures 
will be used as templates for computational modeling of related protein 
homologs to produce structural coverage of a majority of sequenced 
genes.  As it grows, the PSI collection of structures is expected to 
have a significant impact on biological and medical research, in a way 
similar to the human genome project.  These structures will help 
researchers discover the functions of proteins, design better 
experiments, and study key biomedical problems such as protein folding, 
structure prediction, and the organization of protein families and 
folds.  In addition, the results of these studies will be useful for 
faster identification of promising new structure-based medicines, 
better therapeutics for treating both genetic and infectious diseases, 
and development of technology and methodology for protein production 
and crystallography.  For more details about the PSI's goals, 
organization, and benefits, see the PSI mission statement at: 
http://www.nigms.nih.gov/psi/mission.html.  Additional information 
about the PSI can be found under the links listed below. 
 
Prior to initiating the PSI, the NIGMS organized three workshops 
composed of experts from the scientific community to examine 
feasibility, constituent tasks, goals, planning, and target selection 
for this project.  There was general agreement on technical feasibility 
due to advances in the development of high-throughput expression 
systems, protein purification, sample preparation, and structure 
determination by X-ray crystallography and NMR.  It was agreed that all 
tasks could be organized on the large scale required.  A summary of 
these meetings can be found on the NIGMS web site at: 
http://www.nigms.nih.gov/psi/.  Following these workshops and 
discussions by the National Advisory General Medical Sciences Council 
(NIGMS Council), the PSI was initiated.    

The pilot phase of the PSI began in 2000 with a 5-year program for the 
development of research centers.  The principal goal of the pilot phase 
is the development of a structural genomics pipeline for the 
determination of unique protein structures in a high-throughput 
operation.  This program was designed to test all facets and strategies 
for the subsequent production phase of the PSI.  Protein targets are 
chosen as representatives of sequence families and thus provide broad 
structural coverage of sequenced gene products.  Most of the nine pilot 
centers use the 30% sequence identity rule (less than 30% of the 
sequence is identical to the sequence of a known structure) and/or 
profile methods to identify targets for unique protein structures.  
Each pilot center also includes other criteria relevant to feasibility 
and its own scientific mission:  biological function, medical 
relevance, etc.  Over 70% of the structures produced by the PSI pilot 
centers are unique by the 30% sequence identity rule.  Duplication of 
effort is avoided by the public listing of all protein targets (See 
Special requirement B.1).  Major investments in technology and 
methodology development at the nine PSI research centers are making 
each step of experimental structure determination more efficient, less 
expensive, and more likely to succeed.  More information on the nine 
PSI pilot centers and the technological developments can be found at 
the PSI website: http://www.nigms.nih.gov/psi/.  In addition to the PSI 
pilot research center program, the Institute has supported the 
development of methodology and technology underpinning the structural 
genomics through two research programs for individual investigators, 
program projects, and small business grants (PA-99-116 and PA-99-117, 
http://grants.nih.gov/grants/guide/pa-files/PA-99-116.html and 
http://grants.nih.gov/grants/guide/pa-files/PA-99-117.html ).  The 
NIGMS PSI program has also sponsored and/or organized numerous 
workshops for the pilot centers to address technical bottlenecks to 
high-throughput operation.  These workshops covered the following:  
structural genomics bottlenecks, x-ray diffraction, NMR, protein 
production, data deposition, protein production and crystallization, 
data management, homology modeling, and target selection.  Researchers 
in the pilot projects have used a diversity of approaches to overcome 
these problems, and progress has been reported in the workshops, 
scientific meetings, and various publications. Reports of these 
workshops are available at the PSI website at: 
http://www.nigms.nih.gov/psi/meetings.html. 

A central mission of NCRR is to support the creation and dissemination 
of sophisticated technologies and methods critical to a broad range of 
biomedical research.  These technologies serve as a “catalyst for 
discovery” within the broader community.  NCRR has historically 
invested substantial resources in the development of broadly 
accessible, cutting-edge technology for X-ray crystallography and, more 
generally, structural biology.  Participation in this RFA leverages and 
extends these previous investments.

B. Programmatic Summary

Analyses of the results of the pilot research centers by the NIGMS 
staff, PSI Advisory Committee (See Special requirement A.8), and the 
NIGMS Council, have led to the following summary:
1.  Structural genomics pipelines can be constructed and scaled-up.  
This process takes considerable investment in robotic instruments, 
laboratory and data management systems, staff training, etc.  Scaling- 
up takes time and care but can be accomplished. 
2.  High-throughput operation works for many proteins and has led to 
many successful determinations of protein structures.  The development 
and incorporation of robotic instruments, standard protocols, and 
laboratory/data management systems have made notable impact on cost, 
efficiency, success, and time in the passage from DNA sequence to 
structure.  Thus far, most of the proteins that have been solved are 
the “low-hanging fruit” -– easy to express and purify.  
3.  The structural genomics approach of choosing multiple targets is 
successful.  Although the automated approaches are effective, the 
chance of successfully determining a structure for a given target is 
still not high.  However, with multiple targets available for most 
protein families, the likelihood of obtaining the structure of one 
family representative is significantly increased.
4.  Bottlenecks remain for some proteins, such as membrane proteins, 
proteins from human and other higher eukaryotes, and small protein 
complexes.  These challenging proteins are significantly more difficult 
to produce and crystallize and they are the subject of this RFA.  
5.  A coordinated, 5-year target selection policy must be developed.  
The pilot phase approach has worked well, with few duplicate structures 
produced and most of the structures being unique family representatives 
at the time of deposition.  Additional coordination on target selection 
is necessary in PSI-2, with the higher level of protein structure 
output that is expected. 
6.  Homology modeling methods need improvement.  Steady improvement has 
been noted in the methods for comparative homology modeling.  However, 
major improvement is needed to improve the accuracy of the models and 
decrease the number of experimental structures that need to be 
determined.
7.  The impact of the PSI to the broad scientific community should be 
increased.  Benefits from the PSI structures and technologies are 
growing, but more activities are needed to utilize these results fully.

C. Objectives
 
The purpose of this RFA is to announce support for specialized centers 
for methodology and technology development for classes of challenging 
proteins.  These research centers will be the second component of the 
PSI Research Network in structural genomics.  

PSI Research Network: In the production phase, the PSI will consist of 
an interacting network with four components.  
o  In the first component, large-scale research centers will perform 
every step of the structural genomics process starting with DNA 
sequences and leading to the determination of unique protein structures 
in a high throughput operation.  This large collection of unique 
structures is expected to meet the PSI goals for structural coverage of 
sequenced genes.  Each center must also develop technologies and 
methodologies that will make the production and structural 
determination of proteins cheaper, more efficient, and more successful.  
These large-scale PSI research centers are described in a separate 
announcement (GM-05-001). 
o  The second component of the PSI Research Network will focus on the 
development of new methods, technology, approaches, and ideas for 
protein production and structure determinations for especially 
challenging proteins, including membrane proteins, small protein 
complexes, and proteins from human and other higher eukaryotes.  These 
specialized centers will be supported by NIGMS and NCRR. The second 
component of the PSI Research Network is the subject of this 
announcement (GM-05-002) and is described in detail below.
o  The third component of the PSI Research Network will consist of 
specialized centers that determine protein structures from 
microorganisms, tissues, or organ systems related to diseases.  
This third component of the PSI Research Network is being considered as 
an activity of the NIH Structural Biology Roadmap initiative.
o  The fourth component of the PSI Research Network is the development 
and operation of the PSI Knowledge Base.  This component will serve as 
an interface, linking data from the PSI research centers with the PDB 
and other databases related to the PSI.  This information resource will 
be a hub for the PSI.  It will analyze and organize the results from a 
structural genomics perspective.  The NIGMS staff is currently 
developing a mechanism for supporting this component. 
o  Other related research projects can be added to the PSI Research 
Network if determined appropriate by the Director of the PSI Research 
Network.

The components of structural genomics are:
1. Family classification and target selection:  There are several 
schemes of protein sequence clustering for parsing proteomes into 
protein families and for choosing protein targets for structural 
genomics projects.  Target selection for PSI-2 will continue to 
emphasize the selection of proteins as representatives of sequence 
families to search rationally for unique protein structures.  In the 
production phase targets will be selected to maximize structural 
coverage of most sequenced genes, as described below.  
2. Generation of protein for biophysical analyses:  This includes high 
throughput cloning, expression, and purification systems to produce 
large quantities of target proteins in a form suitable for biophysical 
studies.  For PSI, emphasis is on rates of success, efficiency, and 
cost savings.
3. Sample preparation for structural studies:  This crucial 
experimental task has seen significant progress, with significant 
improvement in the ability of structural biologists to crystallize 
proteins and label protein samples for NMR studies. 
4. Challenging protein targets:  Some classes of proteins are still not 
amenable to high-throughput operations.  These include membrane 
proteins, protein complexes, and proteins from human and other higher 
eukaryotes.  These classes of proteins are the main focus of this RFA.
5. Structure determination:  High-resolution structure determination is 
becoming straightforward for many protein samples. Crystallography has 
benefited from the almost universal use of synchrotron beamlines 
coupled with new detectors, cryocrystallographic techniques, multiple-
wavelength anomalous diffraction techniques, and advanced computational 
systems for rapid data collection, processing, and model building.  New 
NMR methods and higher field instruments have increased the size of 
proteins that can be solved by this technique.  Applicants for the PSI-
2 specialized research centers must have expertise and resources in 
either or both of these techniques and are expected to demonstrate 
their access to state-of-the-art synchrotron and/or NMR facilities as 
appropriate.  The NIGMS is currently developing additional beamlines at 
several synchrotron facilities and will likely be able to make 
additional beamtime available to general users and research centers 
funded by this RFA within the next few years.  However, the PSI-2 
specialized research centers are expected to present their own plans 
for data collection and structure determinations.
6. Analyses and dissemination of results:  The research centers will be 
expected to analyze their structures by computational techniques for 
biomedical significance, including functional characterization and 
evolutionary and structural relationships.  Since the goal of this 
initiative is to add to the body of knowledge of protein structure, 
timely release and dissemination of results are crucial.  These results 
include information on strategies for target selections, status of 
these proteins in the structural genomics pipeline, technological and 
methodology findings, high throughput approaches, efficiency, and cost 
analyses.  The research centers are required to have plans for timely 
deposition of coordinates and related data into public databases, 
consistent with NIH policies and PSI programmatic goals. (See Special 
requirements.B.1)
7. Management and administration:  With several components that are 
interdependent, management and administration of the center are 
crucial.  In addition to the usual administrative requirements, the 
leadership of each research center must direct the research and make a 
wide range of decisions about subcontracts, equipment purchases, 
staffing, standard protocols, pipeline priorities and protocols, etc.  
Special PSI requirements, such as cooperative agreement commitments, 
annual reports, attendance at PSI meetings, participation of minority 
scientists and students, outreach to the scientific community, research 
training, intellectual property, participation in the PSI Network, 
etc., must be incorporated by the applicant into the organization of 
each research center. 

Features of specialized centers for technology development:  The 
specialized research centers of the PSI will focus on technology and 
methodology development to overcome major bottlenecks of the structural 
genomics pipeline.  Emphasis will be on classes of challenging proteins 
that are not currently amenable to high-throughput methods.  These 
centers will be expected to at least approach high-throughput operation 
for components of the structural genomics pipeline for these classes of 
challenging proteins by the end of the project.  Success rates, as well 
as costs and efficiency, are important.  Applicants must show that 
their research will have a major impact on the improvement of this 
pipeline and the long-range PSI goal of high throughput production and 
structural determination of all classes of proteins.  In addition, 
applicants must present plans for the development of innovative new 
methods and technologies which have wide applicability to structural 
genomics and are both portable and scalable.  The specialized centers 
must have the capability for all components of structural genomics (see 
list above), but not necessarily in a high-throughput operation.  
Applicants can arrange to carry out some of the structural genomics 
tasks through collaborations and/or subcontracts.  

Another goal, especially in the later years of the project, is the 
production and structural determination of significant numbers of 
members of these classes of proteins.  Target selection for the 
specialized centers must emphasize unique, non-redundant protein 
structures, as described below.  The formation of multidisciplinary 
research teams from multiple institutions and scientific fields is 
strongly encouraged.  Effective plans for management and administration 
of the research centers are crucial.  Rapid release of data into the 
public databases will be required (See Special requirement B.1).

Applicants must describe the major bottleneck(s) to be addressed by 
their center project and the expected impact.  Following discussions 
with the PSI Advisory Committee members, the NIGMS Council, and members 
of the scientific community, the NIH staff has identified three major 
bottlenecks appropriate for these specialized centers.  Applicants are 
encouraged to submit applications for projects that address one or more 
of these three bottlenecks or other major ones.

Topics for specialized centers for technology and methodology 
development.

1. Membrane proteins.  The difficulty of producing and determining the 
structures of members of this large and important class of proteins is 
well known.  Although the expression of membrane proteins is especially 
difficult, other tasks leading to structure determination are also 
hard.  Development of innovative methods for protein production 
(expression, purification, solubilization, etc.), crystallization, and 
structural determination are needed.  The goals of the PSI require a 
considerable increase in the number of unique membrane protein 
structures.  

2. Proteins from human and other higher eukaryotes.  Lower production 
yields for these proteins have limited the number of eukaryotic 
structures in the pilot phase of PSI.  Problems need to be solved 
include inadequate cDNA libraries, unknown ligands and cofactors, post-
translation modification, etc.  

3. Small protein complexes.  In many cases, the expression, 
purification, solubilazation, and crystallization of a protein are 
unsuccessful without the inclusion of the other member or members of an 
interacting pair or small complex.  Co-expression and co-
crystallization are often required for successful structural 
determination.  

4. Other major bottlenecks.  Applicants may propose projects focused on 
other major bottlenecks, but must justify their choice and explain the 
expected benefits to the PSI.  

Target selection for PSI-2:  Since its inception in 1999, the general 
principle for target selection for the Protein Structure Initiative has 
focused on representatives of protein sequence families for which there 
are no known structures.  This approach leads to the determination of 
unique, non-redundant protein structures and is the policy followed in 
the PSI pilot phase.  Although the target selection policy for PSI-2 
begins with this general principle, a more specific policy is required 
for this subsequent and more focused phase.  The NIGMS staff has 
determined that the best specific strategy for target selection for 
PSI-2 is to concentrate on large protein families in order to provide 
the broadest possible structural coverage of sequenced genes.  A 
secondary goal aims directly at biomedical impact with projects 
focusing on specific pathways, organisms, systems, etc.  

These conclusions were reached through a lengthy planning process.  
Prior to the PSI pilot RFA, the NIGMS held a workshop on target 
selection.  More recently, in November 2003, another workshop focused 
on this issue     
(http://www.nigms.nih.gov/psi/meetings/target_selection.html ) and a 
meeting with the PSI Advisory Committee in December 2003 
(http://www.nigms.nih.gov/psi/meetings/psi-advisory-centers.html ).  At 
these meetings, most participants agreed on the strategy for structural 
coverage of sequenced genes by focusing on structural determination of 
large protein sequence families.  Experts from genomic and other 
biomedical fields discussed the appropriate balance of genomic coverage 
and biomedical impact.  A crucial issue in these discussions was the 
appropriate level of the detail, or granularity, of structural coverage 
of sequenced genes.  At coarse granularity, sequence homology 
comparisons are carried out by PSI-BLAST or other profile-based methods 
to produce protein families with distant evolutionary links.  This 
parsing leads to fewer families, each with more members.  As a result, 
fewer experimental structures will be needed for structural coverage of 
sequenced genes, and the structural models generated will be moderately 
accurate for distant homologs in the same family.  On the other hand, 
structural coverage at fine granularity, chosen, for example, as 30% 
sequence identity, would lead to a larger number of sequence families, 
each with fewer members.  At this fine granularity, more experimental 
structures will be required, and the computational models generated 
thereafter would in general be more accurate and suitable for studying 
biological function.  In this workshop and in discussions with the PSI 
Advisory Committee members, the NIGMS Council, and members of the 
scientific community, there was general agreement that the primary goal 
for PSI-2 should the determination of structures representing large 
sequence families to provide structural coverage at coarse granularity 
of sequenced genes.  A secondary goal of a collection of unique, non-
redundant protein structures for specific pathways, organisms, and/or 
groups of proteins was seen to have high scientific value.  

Following these discussions, the NIGMS staff has determined that the 
target selection policy for the PSI should reflect a balance between 
structural coverage of sequenced genes and the exploration of 
biomedically important pathways and systems, as described in the 
previous paragraph.  The large-scale centers will be required to 
address both these goals, providing structural coverage of a majority 
of sequenced genes by the determination of representative structures of 
large protein families at coarse granularity and the collection of 
unique, non-redundant protein structures for structural coverage at 
fine or coarse granularity of protein families from specific pathways, 
organisms, and/or groups of proteins of high scientific value.  In 
choosing targets, the large-scale centers will comply with the 
decisions of the Steering Subcommittee on Target Selection (See Special 
requirements A.7).  Details of the target selection process can be 
found in the RFA for the large-scale centers (GM-05-001).  After the 
initiation of PSI-2, the Steering Committee and the PSI Advisory 
Committee will meet jointly with the NIH staff to determine how to 
carry out target selection for the PSI Network.  Further refinement of 
the target selection criteria by these same groups will occur on a 
regular basis as the PSI-2 project matures.  

Target selection for specialized centers:  The specialized centers must 
propose plans for target selection, consistent with the policies 
described above.  Although the primary goal of the specialized centers 
is the development of methodology and technology for the production and 
structural determination of challenging proteins, these centers will be 
required to produce significant numbers of unique, non-redundant 
protein structures from the class of proteins they have chosen, 
especially in the final years of the project.  Each specialized center 
must propose a plan for selecting targets for production and structure 
determination and structural coverage at granularity consistent with 
the PSI-2 policies and appropriate for its class of challenging 
proteins.  The specialized centers are not directly involved with the 
target selection process of the large-scale centers, but they will be 
required to keep the Steering Subcommittee on Target Selection informed 
of their plans, targets, and structures solved and to participate in 
the overall planning for structural coverage of sequenced genes.  

MECHANISM OF SUPPORT

This RFA will use NIH Specialized Center (U54, Cooperative Agreement) 
award mechanism.  As an applicant you will be solely responsible for 
planning, directing, and executing the proposed project.  This RFA is a 
one-time solicitation.  The anticipated award date is July 1, 2005.  
This RFA uses just-in-time concepts.  This program does not require 
cost sharing as defined in the current NIH Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2003/master_list.htm.

The NIH U54 is a cooperative agreement award mechanism.  In the 
cooperative agreement mechanism, the Principal Investigator retains the 
primary responsibility and dominant role for planning, directing, and 
executing the proposed project, with NIH staff being substantially 
involved as a partner with the Principal Investigator, as described 
under the section "Cooperative Agreement Terms and Conditions of 
Award".  Plans for this program beyond the 5 year award period are 
indefinite and will be considered by the Institute staff with the 
advice of the National Advisory General Medical Sciences Council.  
Applicants can submit applications in response to this RFA for 
specialized technology centers (GM-05-002) and the RFA (GM-05-001) for 
large-scale centers and for the RFA for centers for proteins structures 
related to specific diseases (if the RFA is issued).  If an applicant 
submits more than one of these, the overlap must be clearly noted.  
Only one award will be made to any applicant.

FUNDS AVAILABLE

The NIGMS and NCRR intend to commit up to $27 million in FY2005 to fund 
up to 6 new centers in response to this RFA.  An applicant may request 
a project period of up to 5 years and a budget for the first year of up 
to $4.5 million total costs.  Because the nature and scope of the 
proposed research will vary from application to application, it is 
anticipated that the size and duration of each award will also vary.  
Although the financial plans of NIGMS provide support for this program, 
awards pursuant to this RFA are contingent upon the availability of 
funds and the receipt of a sufficient number of meritorious 
applications.  

Post-award management:  During the course of the grant period, both 
computational and experimental technologies are expected to improve, 
and the rate of progress and focus of work supported by the grant may 
change.  It is expected that the Principal Investigator will make any 
necessary adjustment in scientific direction to accommodate the 
expected scale-up and changing environment.  The NIGMS staff must be 
kept informed of any significant changes.  In order to ensure that the 
project remains focused on appropriate goals, incorporates new 
technological advances, and makes sufficient progress, scientific and 
programmatic visits to the grantee will be conducted at a frequency to 
be determined by NIGMS AND NCRR staff.  In addition, benchmarks for 
progress may be negotiated annually.

The NIGMS AND NCRR may include outside consultants in the annual 
progress review and reduce or withhold funds for failure to meet 
milestones agreed upon by grantees and NIH staff.  A report by the 
NIGMS AND NCRR program director on each research center's progress and 
any recommendations to modify funding will be made annually to the 
National Advisory General Medical Sciences Council.

ELIGIBLE INSTITUTIONS
 
You may submit an application if your institution has any of the 
following characteristics:

o  For-profit or non-profit organizations 
o  Public or private institutions, such as universities, colleges, 
hospitals, and laboratories
o  Units of State and local governments
o  Eligible agencies of the Federal government  
o  Domestic institutions/organizations
o  Foreign institutions are not eligible to apply, but are eligible for 
inclusion as subcontracts with sufficient justification. 

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support.  Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs.   

SPECIAL REQUIREMENTS

A. Special requirements for cooperative agreements  

1.  Cooperative Agreement Terms and Conditions of Award

The following section represents Terms and Conditions that will be 
incorporated into the award statement and will be provided to the 
Principal Investigator, as well as to the appropriate institutional 
official, at the time of award.  The following special terms of award 
are in addition to, and not in lieu of, otherwise applicable OMB 
administrative guidelines, HHS grant administration regulations at 45 
CFR Parts 74 and 92 (Part 92 is applicable when State and local 
Governments are eligible to apply), and other HHS, PHS, and NIH grant 
administration policies:

The administrative and funding instrument used for this program will be 
the cooperative agreement, an "assistance" mechanism (rather than an 
"acquisition" mechanism), in which substantial NIH programmatic 
involvement with the awardees is anticipated during performance of the 
activities.  Under the cooperative agreement, the NIH purpose is to 
support and stimulate the recipients' activities by involvement in and 
otherwise working jointly with the award recipients in a partnership 
role; it is not to assume direction, prime responsibility, or a 
dominant role in the activities.  Consistent with this concept, the 
dominant role and prime responsibility for the project as a whole 
resides with the awardees.

2. Principal Investigator

The Principal Investigator is the scientist who assembles the project 
and is responsible for submitting the application in response to this 
RFA and for performance of the project.  The Principal Investigator has 
the overall responsibility for scientific and technical direction and 
for the administration and overall operation of the PSI specialized 
center.  The Principal Investigator will:
o  Design and direct the specialized center
o  Design technology and methodology development projects to overcome 
major bottlenecks of the structural genomics pipeline, with emphasis 
will be on one or more classes of challenging proteins
o  Propose plans for selecting targets for production and structure 
determination and structural coverage at granularity consistent with 
the PSI-2 policies and appropriate for its class of challenging 
proteins
o  Provide goals and milestones for the project consistent with PSI-2 
goals
o  Commit a substantial level of effort to the project
o  Participate in the cooperative agreement activities and accept PSI-2 
policies and plans
o  Be a member of the PSI Research Network Steering Committee (See 
Special requirement A.6)
o  Attend annual meetings of the Steering Committee and participate in 
its activities, including setting goals and future plans
o  Serve as liaison to the Steering Subcommittee on Target Selection to 
provide coordination and assistance in the selection of protein targets 
o  Participate in the activities of the PSI Research Network
o  Ensure the timely dissemination of information generated by the 
research center to the scientific public
o  Ensure that the structure coordinates and structure factors are 
deposited promptly to the PDB
o  Ensure that results and data are collected, maintained, and 
transferred to appropriate databases, including the PDB; the Target 
Database; and the Protein Expression, Purification, and Crystallization 
Database 
o  Ensure that all appropriate results are provided to the PSI 
Knowledge Base
o  Ensure that the center complies with the intellectual property 
policies of the research center, the NIH, and those developed by the 
PSI 
o  Ensure that materials generated by the research center are shared 
with qualified scientists 
o  Submit periodic progress reports
o  Appoint an External Scientific Advisory Committee of research 
scientists not involved in the consortium to provide independent 
assessment and advice to Principal Investigator and the research center
o  Manage the Center Development Funds, subject to NIH program director 
approval.

3. PSI Research Network Director

The PSI Research Network Director is an extramural staff individual who 
has leadership responsibilities for the management and coordination of 
the PSI Research Network.  The PSI Research Network Director is not a 
member of the Steering Committee and does not direct the scientific 
activities of the PSI Research Network centers (whose direction is the 
responsibility of the Principal Investigator).  The PSI Research 
Network Director will also:
o  Provide advice to the PSI Research Network Steering Committee (See 
Special requirements A.6) on the overall direction of the PSI and on 
meeting the PSI goals and milestones
o  Report on the PSI Research Network activities and progress to the 
directors of NIGMS AND NCRR, the NIGMS Council, and advisory councils 
for other participating NIH institutes and centers
o  Appoint members and a chair of the PSI Advisory Committee, following 
consultation with the director of NIGMS and other NIH staff
o  Evaluate and implement the advice of the PSI Advisory Committee and 
the PSI Research Network Steering Committee for allocating NIH support 
and revising and setting policy
o  Facilitate communication with the scientific community directly 
affected by the PSI
o  Ensure that the Steering Committee and the PSI Advisory Committee 
address issues and concerns raised by the community.  
o  Call and coordinate meetings of the Steering Committee and the PSI 
Advisory Committee
o  Select appropriate additional programs to be added to the PSI 
Research Network as non-voting members of the Steering Committee.

4. NIH Program Directors

The NIH Program Directors are the extramural staff individuals who 
provide normal program stewardship for the PSI Research Network center 
awards.  The NIH Program Directors are not members of the Steering 
Committee and do not direct the scientific activities of the PSI 
Research Network centers (whose direction is the responsibility of the 
Principal Investigator).  The NIH Program Directors will also:
o  Negotiate milestones and goals on throughput and costs with the 
grantees
o  Attend all meetings of the Steering Committee
o  Prepare annual reports on the progress of PSI-2 research centers
o  Provide information to the research center Principal Investigators 
on activities and policies of the PSI Research Network and the NIH
o  Recommend appropriate budgets for the research centers, including 
withholding or reduction of support for failure to meet milestones 
and/or other terms or conditions.

5. NIH Scientific Liaisons

The NIH Scientific Liaisons are representatives of the NIH extramural 
staff who serve on the Steering Committee and have substantial 
scientific/programmatic involvement in the project that is above and 
beyond normal program stewardship.  Each of the NIH institutes and 
centers supporting a PSI Research Network center will have one 
Scientific Liaison.  In addition, one member of the NIGMS staff will 
serve on the Steering Committee and the Steering Subcommittee on Target 
Selection.  This position will be named the Scientific Liaison for 
Target Selection.  The Scientific Liaisons will also:
o  Serve as voting members of the Steering Committee and attend all 
meetings
o  Assume a substantial coordinating role on the Steering Committee
o  Make recommendations to the Steering Committee based upon their 
knowledge of other, related NIH-supported research and resource 
activities
o  Facilitate interactions among the Steering Committee, the PSI 
Advisory Committee, and NIH staff
o  Provide advice and guidance to the Steering Committee to assure that 
the PSI project adheres to the NIH rules and regulations
o  Take on additional responsibilities as negotiated at the time of 
award.
 
6. Steering Committee

This committee is the main governing body of the Protein Structure 
Initiative Research Network.  Membership will include the Principal 
Investigators of the large-scale centers, the Principal Investigators 
of the specialized centers, the NIH Scientific Liaisons, a 
representative of the Protein Data Bank, a representative of the PSI 
Research Network Knowledge Base, and other scientists chosen by the 
Steering Committee.  The NIH Scientific Liaisons will serve as voting 
members of the Steering Committee and attend its meetings.  Total NIH 
representation on the Steering Committee will make up no more than 40% 
of the voting members.  Other members of the NIH staff may also attend 
the Steering Committee meetings.  The Principal Investigators of other 
related structural genomics projects may be added to the Steering 
Committee as non-voting members, as determined appropriate by the PSI 
Research Network Director.  The Steering Committee will:
o  Meet at least annually with the PSI Advisory Committee and the NIGMS 
staff to discuss progress of the PSI Research Network in reaching the 
goals set by the NIGMS/NIH staff and Councils and in meeting the needs 
of the scientific community
o  Elect a non-NIH chair to serve a 2-year term
o  Prepare and publish annual reports on progress in meeting milestones 
and goals of the PSI
o  Develop procedures and policies on PSI Research Network activities, 
including laboratory information management systems, data management 
and deposition, publications, reports, etc. for consideration by the 
PSI Advisory Committee and the NIGMS Council
o  Communicate with the scientific community on scientific and 
technological achievements
o  Organize and appoint the Steering Subcommittee on Target Selection 
o  Serve as the body for coordinating and making decisions on target 
selection
o  Serve as the body for coordinating and making decisions to ensure 
meeting the milestones and goals for the production phase of the PSI
o  Organize and appoint appropriate subgroups to address related 
issues. 

7. Steering Subcommittee on Target Selection

This subcommittee will be composed of the Principal Investigators of 
the large-scale centers, the Scientific Liaison for Target Selection, 
and other representatives as chosen by the Steering Committee.  The 
subcommittee will coordinate the selection of protein targets among the 
large-scale centers.  Representatives of the specialized centers will 
serve as liaisons to the Steering Subcommittee on Target Selection.  
Details of this subcommittee can be found in the RFA for large-scale 
centers (GM-05-001).  
  
8. PSI Advisory Committee

The PSI Advisory Committee is a working group of the National Advisory 
General Medical Sciences Council.  It will advise the Council on the 
management, progress, and plans for the PSI.  This committee will:
o  Meet at least once a year with the Steering Committee and NIH staff 
prior to the submission of the annual progress report 
o  Examine and comment on target selection policy and progress toward 
milestones
o  Provide advice to the Principal Investigators and Steering Committee 
about meeting the PSI goals and plans for future directions
o  Raise issues for consideration by the Principal Investigator and the 
Steering Committee 
o  Comment on the appropriateness of the level of NIGMS support to 
achieve the goals of the project.

9. Goals and Milestones

The PSI-2 will have annual milestones appropriate to the 5-year goal.  
Milestones will be determined through discussions with the Principal 
Investigators, Steering Committee, and NIH staff.  The milestones and 
goals will be refined annually with input from the Steering Committee 
and PSI Advisory Committee.    

10. Reports

The PSI Research Network Steering Committee will produce an annual 
report on the progress made toward the annual milestones and goal.  The 
report will be delivered to the NIGMS staff and PSI Advisory Committee 
within one month of the annual meeting.  

11. Arbitration Panel

A panel formed as needed to review scientific or programmatic 
disagreements (within the scope of the award) that may arise between 
the PSI Research Network and the NIH.  It will be composed of three 
members:  a designee of the Steering Committee chosen without NIH staff 
voting, one NIH designee, and a third designee with expertise in the 
relevant area who is chosen by the other two.  

(End of cooperative agreement terms)

B. PSI Research Specialized Center Special requirements

The NIGMS has adopted several polices that are applicable to these 
structural genomics research centers.  Applicants must present plans to 
adhere to the policies, where appropriate.

1. Data Release and Sharing of Results and Materials.  The PSI 
represents a major scientific endeavor with large amounts of data 
generated in the process of protein structure determination.  The 
primary products of the PSI, structural coordinates, must be deposited 
promptly in the PDB, which has served the scientific community for four 
decades by providing public access to the annotated structural models.  
Other structural results, including, structure factors, must also be 
deposited promptly into the PDB.  Although guidelines developed by NIH 
for research grants 
(http://grants.nih.gov/grants/guide/notice-files/not99-010.html) 
permit NIH Principal Investigators to deposit coordinates and structure 
factors upon publication of results, PSI regulations and programmatic 
goals are more stringent and require these depositions upon completion 
of the structures.  For the start of PSI-2, this will be interpreted 
as receipt by the PDB within four weeks of the coordinate refinements.

In addition, dissemination of results of the research centers is 
crucial to the programmatic goals of the PSI, and applicants should 
plan on sharing findings and their experiences at the annual meetings 
for structural genomics grantees and in other appropriate forums.  This 
includes information on strategies for target selections, status of 
research on these proteins, technological and methodology findings, 
high-throughput approaches, efficiency, and cost analyses.  Grantees 
will be required to develop and maintain a public website showing the 
information listed above, as well as providing it in their annual 
progress reports.  These results must be provided to the PSI public 
website, which contains information on the program and technical and 
scientific results.  

Another database, TargetDB (See TargetDB at http://targetdb.pdb.org/), 
was recently developed by PDB with PSI and contains all the PSI 
centers’ targets and weekly progress toward structure determination.  
This information should avoid duplicative work and assist planning by 
the centers and other structural labs.  The current PSI pilot centers 
are required to provide these data for uploading each week, and this 
policy will continue in PSI-2.  TargetDB has increasingly attracted 
attention of the scientific community.

The NIGMS is developing a database for deposition of information on 
experimental outcome data (both successful and unsuccessful).  These 
data include genome analysis for protein clustering and target 
selection, cDNA cloning, expression vector construction, protein 
production and purification, protein biochemical characterizations, 
crystallization screening, synchrotron and NMR data collection, etc.  
The PSI Research Network centers will be required to provide plans for 
the collection, maintenance, and transfer of experimental results into 
this central data repository.  This database, named the Protein 
Expression, Purification, and Crystallization Database (PepcDB), is 
under development and will contain information on these important 
results and provide a platform for cross-center data mining to 
capitalize on the PSI investment (contact Dr. Norvell at NIGMS for 
updated information).  

In some cases, the proteins and samples generated by these research 
centers will need to be pursued by detailed functional studies by 
scientists both within and outside the research centers that are beyond 
the scope of these awards.  The research centers will be required to 
provide these materials to appropriate investigators.  Currently the 
individual pilot centers have the responsibility for distribution of 
these proteins and samples, but a centralized repository is being 
considered for PSI-2.   

In PSI-2, the PSI Advisory Committee and NIGMS staff anticipates the 
need for a central resource that interconnects all the data and 
resources generated by the PSI with related databases and other 
biological information.  This resource has been named the PSI Research 
Network Knowledge Base.  The PSI research centers will be required to 
make all data available for dissemination by the PSI Knowledge Base. 

2. Management Plan.  The management of a PSI specialized research 
center requires a significant commitment by the senior staff.  The 
Principal Investigator must devote a substantial effort to the project.  
The applicant must propose a management plan that takes into account 
the changes that will occur over the 5-year term of the award. If the 
requested budget includes Center Development Funds (See Special 
requirement B.9), the applicant must explain how decisions on the use 
of these funds will be made by the Principal Investigator and the 
senior staff of the center.

3. Research Training.  Applicants are encouraged, but not required, to 
have plans for research training activities.  One example is the 
involvement of graduate students and postdoctoral associates as part of 
their research staff.  Although many PSI activities involve extensive 
data collection and therefore might not be appropriate as research 
training projects, other activities will be at the cutting edge of 
research and thus would be suitable for graduate thesis research 
training and for postdoctoral projects.   Another example of a research 
training activity is the organization of technical workshops for 
graduate students and postdoctoral associates as potential users of the 
pipeline, materials, and PSI results.

4. Participation of underrepresented minority investigators and 
students.  The research centers are encouraged, but not required, to 
have plans to promote the participation of investigators and/or 
students from underrepresented minority groups. One example is 
organization of summer programs for faculty and/or students from 
minority institutions.  Another example is the solicitation of protein 
targets from faculty at minority institutions for inclusion in the 
center’s structural genomics pipeline and target selection process.

5. Participation of the scientific community.  The primary 
responsibility of the specialized PSI centers is the development of 
methodology and technology for challenging proteins, however they are 
encouraged, but not required, to have plans for activities for the 
participation of the scientific community.  For example, centers could 
designate a limited period of time for the incorporation of special 
projects from outside scientists into the structural genomics pipeline.  
Centers could plan for short-term courses and technical workshops for 
potential users of the pipeline, materials, and PSI results.
6. Intellectual property.  NIGMS and NCRR are committed to making 
results of these projects freely available for use by the entire 
research community and, therefore, released into the public domain.  
Applicants should present plans related to intellectual property rights 
consistent with this policy.  The NIGMS  and NCRR will monitor its 
grantees' activities with respect to patenting the structural results 
and technology developments.
 
The scientific review group will comment, as appropriate, on the plans 
and previously demonstrated success for handling intellectual property 
issues.  Since dissemination of results is a critical aspect of the 
PSI, evidence of the commitment to the sharing of research resources 
and to effective management of intellectual property issues will be 
part of the scientific merit review, as well as an important factor in 
the Institute’s decision to make an award.  Furthermore, these plans, 
after negotiation with the applicant when necessary, will be made a 
condition of the award.  Evaluation of annual progress reports and of 
subsequent renewal applications will include an assessment of the 
effectiveness of the sharing of research resources and managing 
intellectual property issues.

Plans for sharing of research resources and intellectual property must 
make unique research resources readily available for research purposes 
to qualified individuals within the scientific community in accordance 
with the NIH Grants Policy Statement 
(http://grants.nih.gov/grants/policy/nihgps/) and the Principles and 
Guidelines for Recipients of NIH Research Grants and Contracts on 
Obtaining and Disseminating Biomedical Research Resources: Final Notice, 
December 1999 (http://www.ott.nih.gov/policy/rt_guide_final.html and 
http://ott.od.nih.gov/NewPages/64FR72090.pdf).  These documents also 
define terms, parties, responsibilities, prescribe the order of 
disposition of rights, prescribe a chronology of reporting requirements, 
and delineate the basis for and extent of government actions to retain 
rights.  Patent rights clauses may be found at 37 CFR Part 401.14 and 
are accessible from the Interagency Edison web page, 
http://www.iedison.gov.

7. External Scientific Advisory Committee.  Each research center should 
have an external scientific advisory committee of research scientists 
not involved in the consortium to provide independent assessment and 
advice to the Principal Investigator and his/her staff.  This committee 
should be appointed by the Principal Investigator of each research 
center and meet at least once each year.  In order to maximize the pool 
of possible reviewers, the potential (or new) members of the external 
scientific advisory committee should not be contacted or selected until 
after an award has been made.

8. PSI Annual Meeting.  The Principal Investigator and appropriate 
staff of each PSI specialized research center will be expected to 
attend the PSI annual meeting and workshops to discuss progress and 
results.

9. Center Development Funds.  This budget item will provide budgetary 
flexibility in the development and operation of the structural genomics 
pipeline for producing proteins and determining their structures.  It 
will permit the specialized centers to make budget changes within a 
budget year and to explore innovative ideas and new technologies.  
Since reallocation during any budget year between subprojects (often at 
different institutions) is difficult, the Center Development Fund may 
be needed by a specialized center to make major changes and move in new 
directions.  The primary use of these funds must be to support staff 
and purchase equipment and supplies related to the pipeline tasks.  New 
technology and methodology development projects to improve the 
structural genomics pipeline are also appropriate.  Applicants may 
request up to 5% of the total budget annually as a Center Development 
Fund.  If these funds are requested, the applicant must describe the 
process that the center will use to determine its allocation.  All 
expenditures from the Center Development Fund will require NIH staff 
approval.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into 
three areas:  scientific/research, peer review, and financial or grants 
management issues:

o  Direct your questions about scientific/research issues to:

John C. Norvell, Ph.D.
Division of Cell Biology and Biophysics
National Institute of General Medical Sciences
Building 45, Room 2AS.13B, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-0533 
FAX: (301) 480-2004 
Email: norvellj@nigms.nih.gov  

Amy L. Swain, Ph.D.
Biomedical Technology Division
National Center for Research Resources
6701 Democracy Blvd.
Room 964
Bethesda, MD  20892-4874
Telephone (301) 435-0752
FAX (301) 480-3659
Email:  SwainA@mail.nih.gov 

o  Direct your questions about peer review issues to:

Helen R. Sunshine, Ph.D. 
Office of Scientific Review
National Institute of General Medical Sciences
Building 45, Room 3AN.12F, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-2881
FAX:  (301) 480-8506
Email:  sunshinh@nigms.nih.gov

o Direct your questions about financial or grants management matters 
to:

Ms. Grace Olascoaga
Division of Extramural Activities
National Institute of General Medical Sciences
Building 45, Room 2AN.32E, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-5520
FAX:  (301) 480-2554
Email: olascoag@nigms.nih.gov
 
LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that 
includes the following information:

o  Descriptive title of the proposed research
o  Name, address, and telephone number of the Principal Investigator
o  Names of other key personnel 
o  Participating institutions
o  Number and title of this RFA 

Although a letter of intent is not required, is not binding, and does 
not enter into the review of a subsequent application, the information 
that it contains allows IC staff to estimate the potential review 
workload and plan the review.
 
The letter of intent is to be sent by the date listed at the beginning 
of this document.  The letter of intent should be sent to:

John C. Norvell, Ph.D.
Division of Cell Biology and Biophysics
National Institute of General Medical Sciences
Building 45, Room 2AS.13B, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-0533 
FAX: (301) 480-2004 
Email: norvellj@nigms.nih.gov  

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  Applications must 
have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) 
number as the Universal Identifier when applying for Federal grants or 
cooperative agreements.  The DUNS number can be obtained by calling 
(866) 705-5711 or through the web site at 
http://www.dunandbradstreet.com/.  The DUNS number should be entered on 
line 11 of the face page of the PHS 398 form.  The PHS 398 document is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

SUPPLEMENTARY INSTRUCTIONS:

Special application requirements

The research center should be an integrated, coordinated project, with 
various interdependent subprojects that include structural genomics 
components as described above.  These must be fully described and 
justified.  The center must also meet the SPECIAL REQUIREMENTS B.PSI 
Research Center Special requirements.  Collaborations and consortia are 
encouraged.  In such collaborations, the respective contributions 
should be well integrated into the design of the application.  An 
overview section should be prepared that includes an overall 
description that defines the scope and objectives.

The application should have a face page; abstract; project overview 
(which describes the overall program and defines its scope and 
objectives); listing of key personnel; project rationale; subproject 
descriptions; consolidated budget; subproject budgets; biographical 
sketches; investigators' other support; institutional support, 
resources and facilities; and letters of collaboration.

The budget should be no greater than $4.5 million total costs for the 
first year, with annual cost-of-living increases (not to exceed 3%) in 
subsequent years.  The budget should be fully justified and should 
include funds for attending the PSI annual meetings, workshops, 
Steering Committee meetings, and other PSI meetings.  The page limit 
for the research plan (including overview, project rationale, and 
subproject descriptions) is 50 pages total.

The application should provide assurances that the center will: 
o  Participate in the activities of the PSI Research Network 
o  Serve on the Steering Committee and assist in target selection, 
meeting production goals, and planning for the PSI Research Network
o  Submit data to the PSI Research Network Knowledge Base

The application should provide data on protein structures that have 
been solved by the participating investigators during the past five 
years.

The application should provide data on the production of challenging 
proteins by the participating investigators during the past five years.  
  
The application should describe future plans and past success for:
o  Methodology and technology development for the class of challenging 
proteins that are chosen by the center
o  Producing and determining a significant number of unique, non-
redundant protein structures from challenging protein classes
o  Effective management and administration of a research center or 
other large research program 
o  Sharing of results and prompt placement of data in the public 
domain, including deposition of coordinates and structure factors in 
the Protein Data Bank.   

The application should describe plans for:
o  Increasing throughput, efficiency, and success rates and decreasing 
costs for producing and determining the structures of proteins
o  Protein family classification and target selection, consistent with 
PSI-2 policies and appropriate for the class of challenging proteins  
o  Carrying out all the constituent tasks of a structural genomics 
pipeline
o  Evaluating the impact of the project on the structural genomics 
pipeline and the goals of the PSI
o  Developing annual milestones and evaluations for the center and as a 
component of the PSI Research Network
o  Sharing materials generated by this research 
o  Handling intellectual property issues for the center consistent with 
the NIGMS/NIH policies 
o  Sharing of results and prompt placement of data in the public 
domain, including submitting target data and progress to the TargetDB, 
and releasing cloning, protein production, and crystallization results 
into PepcDB.   
o  Providing resource sharing and training to the scientific community.

USING THE RFA LABEL:  The RFA label available in the PHS 398 (rev. 
5/2001) application form must be affixed to the bottom of the face page 
of the application. Type the RFA number on the label.  Failure to use 
this label could result in delayed processing of the application such 
that it may not reach the review committee in time for review.  In 
addition, the RFA title and number must be typed on line 2 of the face 
page of the application form and the YES box must be marked. The RFA 
label is also available at: 
http://grants.nih.gov/grants/funding/phs398/labels.pdf.

SENDING AN APPLICATION TO THE NIH:  Submit a signed, typewritten 
original of the application, including the Checklist, and three signed, 
photocopies, in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application and 
all copies of the appendix material must be sent to:

Helen R. Sunshine, Ph.D. 
Office of Scientific Review
National Institute of General Medical Sciences
Building 45, Room 3AN.12F, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-2881
FAX:  (301) 480-8506
Email:  sunshinh@nigms.nih.gov

APPLICATION PROCESSING: Applications must be received on or before the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the 
applicant without review. 

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and 
funding assignment within 8 weeks.

The Center for Scientific Review (CSR) will not accept any application 
in response to this RFA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application.  However, when a previously unfunded application, 
originally submitted as an investigator-initiated application, is to be 
submitted in response to an RFA, it is to be prepared as a NEW 
application.  That is, the application for the RFA must not include an 
Introduction describing the changes and improvements made, and the text 
must not be marked to indicate the changes from the previous unfunded 
version of the application.  

PEER REVIEW PROCESS  

Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NIGMS.  Incomplete applications will not be 
reviewed.  

Applications that are complete and responsive to the RFA will be 
evaluated for scientific and technical merit by an appropriate peer 
review group convened by the NIGMS in accordance with the review 
criteria stated below.  As part of the initial merit review, all 
applications will:

o  Undergo a process in which only those applications deemed to have 
the highest scientific merit, generally the top half of the 
applications under review, will be discussed and assigned a priority 
score
o  Receive a written critique
o  Receive a second level review by the National Advisory General 
Medical Sciences Council 

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, provide valuable research resources to the 
scientific community, improve the control of disease, and enhance 
health.  In the written comments, reviewers will be asked to evaluate 
the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  
The scientific review group will address and consider each of the 
following criteria in assigning the application’s overall score, 
weighting them as appropriate for each application. 

o  Significance 
o  Approach 
o  Innovation
o  Investigator
o  Environment

SIGNIFICANCE:  Will the technology and methodology development of the 
research center address the bottleneck chosen by the center?  How 
exportable are the strategies and technologies that will be developed 
by this center?  

APPROACH:  What is the likelihood that the applicant will operate a 
successful specialized research center?  Are there well-designed plans 
for developing innovative methodologies and technologies for the 
production and structural determination of challenging proteins?  Is 
the center likely to produce and determine the structure of a 
significant number of proteins from classes of challenging proteins?  
Are the goals, milestones, and organization of the center appropriate?  
Does the applicant acknowledge potential problem areas and consider 
alternative tactics?  Are plans for protein family classification and 
target selection, including plans for its applicability to the PSI 
Research Network, reasonable?

INNOVATION: Does the project employ novel and innovative concepts, 
approaches or methods?  

INVESTIGATORS: Are the investigators appropriately trained and well 
suited to carry out this work?  Do the investigators have experience 
and plans for operation of all components included in the structural 
pipeline?  Is the work proposed appropriate to the experience level of 
the Principal Investigator and other researchers?  Does the Principal 
Investigator have the management, administrative skills, and experience 
appropriate for a large research project?  

ENVIRONMENT: Does the scientific environment in which the work will be 
done contribute to the probability of success? Do the proposed 
experiments take advantage of unique features of the scientific 
environment or employ useful collaborative arrangements? Is there 
evidence of adequate institutional support?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the 
following items will be considered in the determination of scientific 
merit and the priority score:

o  Plans and assurances that the Principal Investigator will serve on 
the Steering Committee and assist in target selection, meeting 
production goals, and planning for the PSI Research Network
o  Plans for increasing throughput, efficiency, and success rates and 
decreasing costs for producing and determining the structures of 
challenging proteins
o  Plans for handling intellectual property issues, for sharing results 
and materials generated by this research, and for prompt placement of 
data in the public domain, including deposition of coordinates in the 
Protein Data Bank and placement of appropriate data in the PSI Research 
Network Knowledge Base
o  Plans for management of the Center Development Fund, if this was 
requested in the budget.

ADDITIONAL REVIEW CONSIDERATIONS

Sharing Research Data 

Applicants requesting more than $500,000 in direct costs in any year of 
the proposed research must include a data sharing plan in their 
application. The reasonableness of the data sharing plan or the 
rationale for not sharing research data will be assessed by the 
reviewers. However, reviewers will not factor the proposed data sharing 
plan into the determination of scientific merit or priority score. 
(http://grants.nih.gov/grants/policy/data_sharing )

BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date: September 10, 2004
Application Receipt Date:  October 15, 2004
Peer Review Date:  February 2005
Council Review:  May 2005
Earliest Anticipated Start Date:  July 2005

AWARD CRITERIA

Criteria that will be used to make award decisions include:

o  Scientific merit (as determined by peer review)
o  Availability of funds
o  Programmatic priorities, including the uniqueness of the proposed 
center to the overall goals of the PSI-2.

REQUIRED FEDERAL CITATIONS 

SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking $500,000 or more in 
direct costs in any single year are expected to include a plan for data 
sharing or state why this is not possible. 
http://grants.nih.gov/grants/policy/data_sharing  Investigators should 
seek guidance from their institutions, on issues related to 
institutional policies, local IRB rules, as well as local, state and 
Federal laws and regulations, including the Privacy Rule.  

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 
The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application.  In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and 
proposals for NIH funding must be self-contained within specified page 
limitations.  Unless otherwise specified in an NIH solicitation, 
Internet addresses (URLs) should not be used to provide information 
necessary to the review because reviewers are under no obligation to 
view the Internet sites.  Furthermore, we caution reviewers that their 
anonymity may be compromised when they directly access an Internet 
site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of 
"Healthy People 2010," a PHS-led national activity for setting priority 
areas.  This RFA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.healthypeople.gov/.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject 
to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.  Awards are made under the 
authorization of Sections 301 and 405 of the Public Health Service Act 
as amended (42 USC 241 and 284)(cite appropriate authorizations) and 
under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92 (cite 
relevant regulations).  All awards are subject to the terms and 
conditions, cost principles, and other considerations described in the 
NIH Grants Policy Statement.  The NIH Grants Policy Statement can be 
found at http://grants.nih.gov/grants/policy/policy.htm 

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the use of all tobacco products.  In 
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits 
smoking in certain facilities (or in some cases, any portion of a 
facility) in which regular or routine education, library, day care, 
health care, or early childhood development services are provided to 
children.  This is consistent with the PHS mission to protect and 
advance the physical and mental health of the American people.

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NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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