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 ongoing projects include: - Constrained Molecular dynamics with electron microscopy images. - Extended Isotropic Periodic Sum Method for Heterogeneous Systems - vibrational subsystem analysis (VSA) method for coupling global motion to a local subsystem while including the inertial effects of the environment. - Extended the MSCALE facility to support Hessian evaluations - QM/MM extensions to efficiently support mobile block Hessian (MBH) methodology - Langevin Network Model (LNM) - New Hamiltonian replica-exchange method based on extending the TIGER method - Calpha-Side Chain Model (C-SCM) coarse grained representation of. - constant-force replica exchange - Molecular Transfer Model, which allows for the accurate prediction of protein properties as a function of osmolyte type and concentration, and pH. - Electron Microscopy and Tomography Image Processing - Development of electric density map docking utility (EMAP) - 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 with Q-Chem Dr. Wu has been developing constrained Molecular dynamics with electron microscopy images. A constraint dynamics algorithm is developed to study conformational change of biological macromolecular systems according to electron microscopy images with fully flexible atomic models. All-atom macromolecular systems are simulated with incorporated map constraint to produce best fitting conformations and the trajectories provide clues for conformational change pathways. This approach makes full use of experimental image information and state of art of molecular dynamics simulations. This method provide to efficient tool to assist multiple state study of protein dynamic processes. Dr. Wu has also enhanced the Isotropic Periodic Sum Method so that is works well for Heterogeneous Systems. Based on the fact that 3D IPS can well describe the long-range interactions of a heterogeneous system with a local region larger than the heterogeneity scale, this work presents a method to use 3D IPS to calculate long range interactions for all kinds of simulation systems, including homogeneous, heterogeneous, and finite systems. This method splits long range interactions into two parts, a short-range part and a long-range part. The short-range part is calculated by summing over atom pairs within a cutoff range (about 10 ). The long-range part is calculated using the fast Fourier transform (FFT) technique. This method is applied to electrostatic and vdw interactions for both periodic and none-periodic systems. Example simulations demonstrate this method can accurately and efficiently calculate long range interactions for molecular simulation. Dr. Woodcock has been working on the development of a new vibrational subsystem analysis (VSA) method for coupling global motion to a local subsystem while including the inertial effects of the environment. The premise of the VSA method is a partitioning of a system into a smaller region of interest and a usually larger part referred to as environment. This method allows the investigation of local-global coupling, a more accurate estimation of vibrational free energy contribution for parts of a large system, and the elimination of the tip effect" in elastic network model calculations. Additionally, the VSA method can be used as a probe of specific degrees of freedom that may contribute to free energy differences. The VSA approach can be employed in many ways, but it will likely be most useful for estimating activation free energies in QM/MM reaction path calculations. Dr. Woodcock has recently extended the MSCALE facility (general multiscale modeling functionality previously added to CHARMM) to support normal mode analysis. This extension works (automatically) in both cases where analytic second derivatives are available and where these have to be computed numerically; CHARMM is the only package that has this functionality. Dr. Woodcock in collaboration with Dr. Yihan Shao and Ms. An Ghysels (Ghent University) have been working on the implementation and testing of a QM/MM extension to the previously published mobile block Hessian (MBH) methodology. This extension makes it possible to study systems that were previously too computationally demanding by reducing the number of degrees of freedom that have to be evaluated during the QM/MM Hessian calculation. 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. 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. Mr. Miller has taken the lead in developing the Langevin Network Model (LNM) that combines the Elastic Network Model (ENM) with the Langevin Mode method developed by Lamm and Szabo. Solvent friction can affect the behavior of biological macromolecules, but this force is not included by standard normal mode analysis. By combining Langevin modes with a coarse grained model (ENM), the LNM captures the effect of friction while keeping simulations small enough to be run on inexpensive hardware. This method has also been used to study the protein myosin II motor protein. Dr. Itoh has developed a new Hamiltonian replica-exchange method. This method is a combination of the standard Hamiltonian replica-exchange method and the TIGER (Temperature Intervals with Global Energy Reassignment) method that was developed by collaborators at Clemson University. It has the advantage that effective samplings can be realized in appropriate reaction-coordinate space, although the original TIGER method can sample effectively the temperature space. Evaluation of the new method is ongoing. Mr. O'Brien has further developed and extended the Calpha-Side Chain Model (C-SCM) representation of proteins for simulations. The C-SCM is a coarse-grained model for proteins in which amino acids are represented with two interaction sites (beads), one located at the C-alpha carbon position on the protein backbone and one located at the center-of-mass of the side chain provided the amino acid has a side chain. The C-SCM is powerful because it allows effectively ergodic simulations of protein folding to be carried with many folding/unfolding transitions observed in a single trajectory. To further enhance sampling, Mr. O'Brien has further developed his replica exchange code to carry out additional types of replica exchange and improve usability. His code allows constant-force replica exchange useful for simulating single-molecule force experiments, analogous to what is done in wet labs using Atomic Force Microscopy or Laser Optical Tweezers. Mr. O'Brien has also developed a versatile software package that implements the Weighted Histogram Analysis Method (WHAM) which gives optimal estimates of equilibrium protein properties based on molecular simulations. This package includes an implementation of the Molecular Transfer Model, which allows for the accurate prediction of protein properties as a function of osmolyte type and concentration, and pH.