DEVELOPMENT OF THEORETICAL METHODS FOR STUDYING BIOLOGICAL MACROMOLECULES

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New theoretical techniques are being developed and characterized. These efforts are usually coupled with software development, and involve the systematic testing and evaluation of new ideas. This development is driven by current needs and interests. Specific projects include: - Development of Ewald summation net-charge corrections - Evaluation of binding energy prediction methods - Development of the REPLICA/PATH method for determining reaction paths in complex systems using simulated annealing - Development of combined Quantum Mechanical/Molecular Modeling (QM/MM) potentials and algorithms (gaussian blur of MM charges) - Evaluation of alternate treatments of QM/MM interfaces - Development of grid-based density functional methods for QM/MM modeling - Development of flexible constraints MD techniques - Symplectic methods for molecular dynamics simulations - Rational drug design: shape descriptor facility for CHARMM - Testing of Locally Enhanced Sampling (LES) for conformational searching Although many of the parameter sets and models that are generally available are of the quality required for accurate simulation of macromolecular systems, there remains the need to weigh the relative merits of these sets for the specific types of systems studied in the MGS. There are also numerous details such as the treatment of water and long-range electrostatics. Ongoing projects include: - Development and use of a polarizable and flexible water model - Approximation of long-range interactions in macromolecular simulation using variants of the Ewald sum and the particle mesh Ewald methods - Evaluation and comparison of implicit and explicit water models for simulations examining the hydration of proteins - Evaluation of parameter sets