Nanomedicine

Center for Protein Folding Machinery

2006 Progress Report – Executive Summary

The Center for Protein Folding Machinery (proteinfoldingcenter.org) was established in the fall of 2005. The currently 11 active members are drawn from Baylor College of Medicine, Stanford University, UCSF, MIT and LBNL. Our Center is a virtual one. We communicate among our members and their staffs via internet. We have relied heavily on the Nanohub, a video conferencing infrastructure, at Purdue University where we used it routinely as a cyber-meeting room to chat and share documents and data. Members of each of the research groups have traveled to other sites for an extended period of discussions and collaborations. In addition, we have held two retreats in the past year. The second one held in Stanford University in April 2006 was attended by over 60 participants including all the PIs for 2.5 days. The quality of presentations and discussions was as high as any scientific meeting could have hoped for. The power point presentations of all the participants are archived in our web site (proteinfoldingcenter.org).

Our Center is managed by an executive committee which sets research and funding priority to each of the participating labs. We have assembled two prominent scientists as our external consultants to critically assess our approach and progress annually. They attended our annual retreat and provided critical comments and useful suggestions. We plan to expand the membership of our external advisory committee in the future year as the complexity and diversity of our team expand. A part-time administrative assistant has handled satisfactorily all fiscal and travel events for the entire team.

The major workforce of our Center is the graduate students and postdoctoral fellows. Presently, we have 9 graduate students and 10 postdoctoral fellows who are working within the scope and interest of our Center. Most of their salaries are not paid by the Center fund. Their active participations are critical to the success of our program. We plan to expand the recruitment of talented fellow to join our research enterprise. We have implemented a summer undergraduate research program with which the students would work under the supervision of a faculty mentor and lab staff. We are pleased to attract three academically superb undergraduates from three different institutions across the country. We believe that this is a great way to nurture the next generation of scientists who would be comfortable to work at the interface of biomedical and engineering/physical sciences.

Our Center is taking an active role in promoting the emerging discipline of nanomedicine. The PI has organized a symposium on Nanomedicine in the 2007 annual meeting of the Biophysical Society. We are also making an effort to develop collaborative research with other NDCs. We are implementing a systematic approach for establishing collaboration between our members and those of the other NDCs The PIs of our NDC have been making big leads not only in their own research endeavors but also taking time to interact with other investigators within our NDC. We are particularly pleased to establish 8 new collaborations among our investigators which do not exist prior to the establishment of this NDC. The major research accomplishments of our Center in year 01 include

• Improving the hardware in the ABEL trap device to be able to trap single chaperonins in buffer (Moerner).
• Probing dynamics of chaperonin and substrates by single-molecule imaging and targeted probing sites (Moerner and Frydman)
• Generating the first pseudo atomic models of the TRiC chaperonin in close and open conformations by a hybrid of cryoEM and homology modeling (Chiu, Ludtke, Sali and Frydman)
• Implementing new algorithms for particle orientation identification to allow higher resolution reconstruction from cryoEM of chaperonin at different chemical states (Ludtke)
• Improving the accuracy of homology model building by iterative alignment of the sequence and cryoEM density map (Sali and Chiu)
• Integrating computational methods for the in silico design of an adaptor molecule interface between a tumor suppressor protein and the TRiC chaperonin based on experimental data (Kortemme and Frydman)
• Introducing new energy function to estimate the molecular motion of subunits in a large nanomachine (Levitt) and applying it cryoEM structures of the chaperonin (Levitt, Ludtke and Chiu)
• Implementing new algorithm in predicting protein folding by including solvent and spatial confinement constraints (Pande).

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