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 ongoing projects include: - Development of electric density map docking utility (EMAP) - The core-weighted fitting method to construct molecular assemblies from EM maps - Molecular modeling using low resolution maps - Thermodynamic properties in Self-Guided Molecular Dynamics (SGMD) simulations - Isotropic Periodic Sum method for the calculation of long range interactions - Anisotropic long range corrections for truncated van der Waal (LJ) interactions - Development and validation of methods for simulating interfacial systems in P21 boundary conditions (single surface) - Development of methods for examining reaction mechanism in complex systems - Unbiased forced sampling of complex conformational transitions and estimation of the potential of mean force along the reaction pathway - Development of the REPLICA/PATH method for determining reaction paths in complex systems using simulated annealing - Development of lineal scaling methods for ab initio combined Quantum Mechanical/Molecular Modeling - Enhancements of QM/MM potentials (using Gaussian delocalize MM charges, double link atom method) - GAMESS-UK and CHARMM integration for QM/MM applications - Density functional QM/MM using a double link atom interface - Development of accurate interaction energy calculations for macromolecules - Development of a rapid search strategy for docking two macromolecules Considerable efforts has been aimed at molecular modeling and structure determination using low resolution maps. This involved the development of electric density map docking utility (EMAP) module in CHARMM. we have developed a core-weighting approach to fit atomic structures into low resolution EM maps of biomolecular assembly with multiple components. The proposed core-weighted correlations have significantly improved sensitivity to distinguish the correct fit when compared with more traditional correlations. The construction of a molecular model for a complex macromolecular assembly is thus simplified from a many-body search problem to a series of single-body search problems, making the computational search for the correct fit much easier. Combined with the core-weighted correlation function, a grid-threading Monte Carlo (GTMC) approach is developed to search the best fit efficiently. Quantum mechanical/molecular mechanical (QM/MM) techniques are extremely useful in the theoretical examination of competing reaction pathways in enzyme mechanisms. GAMESS-UK has been tightly integrated into CHARMM to allow studies of catalytic paths in small molecules and enzyme complexes. This extends the QM/MM suite within CHARMM since GAMESS-UK provides DFT methods. Dr. Woodcock has primary been focused on developing and maintaining QM/MM interfaces as well as adding functionality to the existing QM/MM Replica/Path and Nudged Elastic Band (NEB) methods. A recent QM/MM enhancement added support for the ab initio software package Q-Chem to CHARMM. We have also developed a pathway sampling techniques to reproduce the potential of mean force (PMF) of complex chemical/biochemical reactions with reduced computational costs.
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