Development Of Theoretical Methods For Studying Biological Macromolecules

Heart, Lung, And Blood Institute

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Abstract

Specific ongoing development projects include:[unreadable] - New MSCALE multi-scale method[unreadable] - Dual force field methods, combining CHARMM and CFF[unreadable] - Development of the coarse-grained Elastic Langevin Mode method (ELM)[unreadable] - Isotropic Periodic Sum for anisotropic systems[unreadable] - Protein-protein docking with Map Objects[unreadable] - Development of boron parameters[unreadable] - Development of the mixed elastic network model (MENM)[unreadable] - Extension of the DGMM methods to Q-Chem [unreadable] - Incorporating the QM/MM micro-iteration scheme[unreadable] - Full hybrid quantum mechanical/molecular mechanical (QM/MM) normal mode analysis. [unreadable] - Extending the vibrational subsystem partitioning[unreadable] - Developing the SEMS (Single Environment, Multiple State) method[unreadable] - Coarse-grained models for studying large biomolecular systems[unreadable] - Two complimentary methods for studying osmolyte effects on protein folding kinetics and thermodynamics[unreadable] - Implementation of four different types of replica exchange[unreadable] [unreadable] New MSCALE multi-scale method: The new multi-scale command has been implemented into CHARMMM program. This allows to run independent but connected subsystems within the CHARMM framework. The subsystems can use either CHARMM jobs with independent input scripts or a variety of other computational chemistry codes, such as ab initio or molecular mechanics programs. Currently the following ab initio programs are already implemented: NWCHEM, MolPro, Gaussian, Psi and MPQC. The implementation also allows one to mix different force fields on susbsystems and also different system scales, such as coarse grain, atomic force fields and QM at the same time. The controlling CHARMM script can run in parallel and the subsystems may also be independent parallel jobs.[unreadable] [unreadable] Dual force field methods, combining CHARMM and CFF: CHARMM has been extended to allow the simultaneous use of two different force fields for different portions of a single system. The motivation is to properly address the solid-liquid multiphase system of protein adsorption on synthetic polymer surfaces. In doing so, the CFF implementation in CHARMM has been fully decoupled so that other class-II force fields such as PCFF, and COMPASS may be also used. The interphase interaction potential is being tuned with experimental peptide adsorption data on Poly-lactic acid (PLA) polymers.[unreadable] [unreadable] Isotropic Periodic Sum for anisotropic systems: This work presents a continue development in the isotropic periodic sum (IPS) method. The IPS method was developed for homogenous systems and can accurate describe long-range interaction of homogenous systems. For accurately calculating long-range interaction of periodic membrane systems, we developed the 1+2D IPS method. To generalize the IPS method, we further developed a universal IPS method, which can be applied to all kinds of simulation systems and is computational more efficient than PME method. [unreadable] [unreadable] Protein-protein docking with Map Objects: We developed a method that uses map objects for molecular modeling to efficiently derive structural information from experimental maps, as well as conveniently manipulate map objects, 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. Dr. Gruschus is applying this method in his structure study of the perioxiredoxin complex. [unreadable] [unreadable] Development of boron parameters: Dr. Larkin has been developing parameters for boron containing moieties-key substrates with significant medical relevance-using quantum chemical methods. The purpose of this work is to characterize the boron atom to allow for its incorporation into ongoing molecular dynamical studies of the inhibition mechanisms of ?-lactamases as well as proteasomes responsible for cancer. Boron is increasingly important in drug development, and these boron parameters being developed and incorporated into the CHARMM parameter sets.[unreadable] [unreadable] Development of the mixed elastic network model (MENM): In collaboration with Dr. Hummer, we have developed a mixed elastic network model (MENM) to study large-scale conformational transitions of proteins between two (or more) known structures, which is demonstrated by applying it to the large-scale conformation changes of the motor proteins KIF1A kinesin and myosin II. The MENM formalism is computationally efficient and generally applicable even for large protein systems that undergo highly collective structural changes.[unreadable] [unreadable] Extension of the DGMM methods to Q-Chem: Extending the DGMM (Delocalized Gaussian Molecular Mechanics, Das, et al. J. Chem. Phys. 117, 23, 2002) to the high performance ab initio software package Q-Chem involves the implementation of new three center integrals and their subsequent derivative integrals. The point charges now are treated as blurred Gaussian functions rather than point charges. The original implementation of this scheme was not consistent with newer QM and QM/MM techniques available within the CHARMM/Q-Chem combination. [unreadable] [unreadable] Incorporating the QM/MM micro-iteration: We have implemented the recently developed QM/MM micro-iteration scheme of Kasnter (Kastner, Thiel, Senn, Sherwood, Thiel, J. Chem. Theory Comp., 3, 1064, 2007). This method introduces a set of charges that have been fit to the quantum mechanical density to act as an approximate QM region. In addition, a classical gradient correction is used to smooth the transition between the fit charge energy surface and the quantum surface. This allows for fast relaxation of the classical regions without the re-computation of the quantum wavefunction. This scheme has been implemented and extended to for use with CHARMM's reaction path methods (i.e. Replica Path and Nudged Elastic Band).[unreadable] [unreadable] Full hybrid quantum mechanical/molecular mechanical (QM/MM) normal mode analysis: Extending the work of Cui and Karplus (Cui and Karplus; J. Chem. Phys. 112, 3, 2000), we have implemented full hybrid quantum mechanical/molecular mechanical (QM/MM) normal mode analysis. We have extended Q-Chem to perform full analytic second derivatives of the quantum mechanical energy with respect to all atomic centers (both classical and quantum) and interfaced this ability into CHARMM. In addition, we now have the ability to perform both restricted and unrestricted HF and DFT analytic second derivatives, which is functionality that did not previously exist. [unreadable] [unreadable] Extending the vibrational subsystem partitioning: We have extended our new vibrational subsystem analysis technique to include inertia effects of the environment. Not only can be used to probe important global motions in proteins and examine how they influence locally defined regions of the protein of interest, but it can be used to estimate changes in vibrational free energy even for large complex systems.[unreadable] [unreadable] Developing the SEMS (Single Environment, Multiple State) method: We created a new method that is able to examine multiple states of a given protein in a consistent manner. This involves the simultaneous optimization of several states with a single environment. The environment "sees" the average of all states. This restriction allows the direct approximate comparison of different QM states without the usual diversity seen in the environment.[unreadable] [unreadable] Mr. O'Brien has developed software to carry out sereveral types of advanced sampling techniques using CHARMM. Systems with a large number of degrees of freedom often suffer from poor sampling. To enhance sampling of these systems Mr. O'Brien has implemented four different types of replica exchange (REX).