The overall goal of the Computational Resource for Structural Biology is to develop and apply new methods for structure prediction, structure refinement, and mechanistic studies in the context of protein and drug design. The following specific aims are proposed. Development of computational modules and methods in the following areas: 1) Efficient analysis of molecular diversity/similarity of large chemical databases in the context of combinatorial chemistry/database mining, via clustering and pattern recognition, and development of descriptors. 2) Simulation techniques for accurate prediction and analysis of dynamics and thermodynamics of protein-ligand interactions. These will consist of molecular dynamics simulations and computation of solvation free energy with the continuum dielectric model. 3) Hierarchical molecular simulation algorithms combining quantum mechanics and classical mechanics , including density functional theory, molecular orbital methods, and polarizable molecular mechanics. New development will focus on a new interface between classical and quantum mechanics, and computational methods and parameters for application of a polarizable force field. 4) New tools for structure analysis and refinement based on statistical geometry.
