Multiscale Modeling Tools for Structural Biology

Multiscale Modeling Tools for Structural Biology

The Scripps Research Institute 10550 North Torrey Pines Road La Jolla, CA 92037 mmtsb.scripps.edu Grant No. P41 RR012255

Principal Investigator and Contact Charles L. Brooks, III, Ph.D. 858-784-8035; Fax: 858-784-8688

Research Emphasis

Problems in structural biology increasingly require researchers to move between models of low resolution and detailed atomic models to fully explore and exploit experimental information. This resource focuses on development of new and integrated approaches to multiscale modeling, with an emphasis on modeling large-scale assemblies of nucleic acids and proteins with nucleic acids, developing methods that combine lattice-based dynamic Monte Carlo and all-atom molecular dynamics, studying physical processes involved in and developing models for the interactions associated with virus assembly, and establishing new tools for the combined treatment of crystallographic and low-resolution structural models from cryo-electron microscopy. These research threads are tied together through the development and distribution of computer codes to make such multiscale simulations and modeling readily accessible to the scientific community at large.

Current Research

Current research involves modeling very large conformational changes occurring in proteins, nucleic acids, and their assemblies; developing methods and models to explore virus swelling and associated large-scale capsid dynamics during viral maturation; exploring meso-scale distortions of molecular assemblies with the use of low-resolution data from electron microscopy, in the absence of any atomic level structural information; providing links between low-resolution images of functional states of the ribosome during translocation and the near-atomic structural distortions that make up these motions; and characterizing protein-protein interfaces in assembled virus capsids from an energetic and structural standpoint, providing a basis for understanding large-scale molecular assembly. Additional research involves the ongoing development of methods for, and applications to, protein folding, loop, and homology modeling, including participation in CASP5, to perfect and Aharden@ physics-based approaches to structural genomics, and the development and testing of software to extend the range of atom-based modeling methods to larger systems.

Resource Capabilities

Instruments

This resource is equipped with high-performance parallel Linux clusters of 32 and 64 processors as well as several dual-processor Silicon Graphics graphics servers. Large-scale modeling and simulation studies are performed on The Scripps Research Institute's servers, which include a 256-node SGI Origin cluster.

Software

Software under development includes lattice-based Monte Carlo sampling codes, nab (a software package to rapidly construct nucleic acid structures at atomic resolution), yammp (a molecular mechanics and modeling code directed toward low-resolution modeling of RNA and DNA), SITUS (for multiscale modeling of atomic and cryo-electron microscopy structural models), X-ray visualization and refinement software, and modules for CHARMM and AMBER. Much of this software is integrated for large-scale "ensemble" modeling, as relevant to structural genomic efforts, through the tool set. The tool set, a suite of Perl libraries and routines that integrate and control the execution and management of large molecular simulations, is available at the Multiscale Modeling Tools for Structural Biology Web site