Development Of Theoretical Methods For Studying Biologic

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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 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 - Efficient approach 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) - Examining hydrogen bonding in high-resolution protein structures a new method to assess NMR protein geometry - Examining amide proton shift tensor using an ab initio study of dependence on local protein structure - 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 combined Quantum Mechanical/Molecular Modeling (QM/MM) potentials (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 - Evaluation of alternate treatments of QM/MM interfaces - Development of accurate interaction energy calculations for macromolecules - Development of a rapid search strategy for docking two macromolecules - Development of efficient and accurate solvation model using aqueous solution simulation to provide solvation force information. 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. The laboratory has developed the 'Double link atoms with gaussian blur (DLA/DGMM)' technique for the purpose of studying 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. In collaboration with Prof. Toshiko Ichiye, there is an ongoing effort to refine and further develop a new potential energy function for liquid water, which is crucial for accurate computer simulations of biological molecules in realistic environments. The water model, which is referred to as the soft sticky dipole (SSD) model, is both faster and more accurate than currently used models. Currently, the focus is on adding electronic polarizability into SSD water, which will enhance the ability to model water in specialized environments such as inside membrane pores and channels or near metal sites.