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 - Isotropic Periodic Sum method for the calculation of long range interactions - 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 - Enhancements of QM/MM potentials (using Gaussian delocalize MM charges, double link atom method) - Q-Chem and CHARMM integration for QM/MM applications - Development of accurate interaction energy calculations for macromolecules - Development of a rapid search strategy for docking two macromolecules Computational Study Of Super Molecular Assemblies with Map Objects. 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. When dealing with biomolecular assemblies of millions of atoms, atomic description of molecular objects becomes very computational inefficient. We have introduced map objects to CHARMM to facilitate molecular modeling studies which derive structural information from experimental maps. This allows us to conveniently manipulate map objects and perform conformational search directly using map objects. This implementation enables CHARMM to manipulate map objects, including map input, output, comparison, docking, etc. Particularly, we implemented the core-weighted correlation functions to effectively recognize correct fit of component maps in complex maps, and the grid-threading Monte Carlo search algorithm to efficiently construct complex structures from electron density maps. Using a T-cell receptor variable domain as an example system, we showed the application of the EMAP module to model an energetic optimized complex structure according to a complex map. This EMAP module serves as a bridge to between high resolution atomic structures and low resolution map information. Isotropic Periodic Sum: A Method for the Calculation of Long-Range Interactions. The IPS method is an accurate and efficient approach to the calculation of long-range interactions for molecular modeling and simulation. This method defines a local region for each particle and describes the remaining region as images of the local region statistically distributed in an isotropic and periodic way, which we call isotropic periodic images. Different from lattice sum methods that sum over discrete lattice images generated by periodic boundary conditions, this method sums over the isotropic periodic images to calculate long-range interactions, and is referred to as the isotropic periodic sum (IPS) method. The IPS method is not a lattice sum method and eliminates the need for a reciprocal space sum. Several analytic solutions of IPS for commonly used potentials are presented. It is demonstrated that the IPS method produces results very similar to that of Ewald summation, but with three major advantages, (1) it eliminates unwanted symmetry artifacts raised from periodic boundary conditions, (2) it can be applied to potentials of any functional form and to fully and partially homogenous systems as well as finite systems, (3) it is more computationally efficient and can be easily parallelized for multiprocessor computers. Therefore, this method provides a general approach to an efficient calculation of long-range interactions for various kinds of molecular systems. Electron Microscopy and Tomography Image Processing An automatic map alignment algorithm is developed to obtain high quality tomography image from noisy tomography volume map. The Local Maximum Clustering method developed from this lab is used to classify the volume maps from tomography to created initial template of the following alignment. The Grid-Threading Monte Carlo method was used to search for the best alignment and the final aligned maps are averaged based on the alignment quality to produce an averaging image. This method is highly efficient and reduces the alignment time by one or two orders of magnitude. Also, this method avoids the arbitrary in initial template. This method has been successfully applied to experiment data to obtain tomography images. 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. In another study, Dr. Zheng has developed a new method that predicts the directionality of a protein conformational change given the crystal structure for its initial state and a small number of pair-wise distance constraints for the end state. I computed the structural displacement in response to a perturbation to the system energy that incorporates the given distance constraints as restraints, which were found to compare well with the observed conformational changes for a list of test cases. Part of Dr. Klauda?s work involves the study of protein folding using the Self-Guided Langevin Dyanamics (SGLD) (4). The folding pathways of several small design peptides and the native protein G are being studied with explicit solvent. The efficiency of conformational sampling and folding pathways using SGLD has been verified for these solvated systems, which previously this method was only tested on unsolvated peptides.
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