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 projects include: - Enhancements in the development of Particle Mesh Ewald (PME) methods - Evaluation of Ewald summation net-charge corrections (PME) - Calculating free energies with Ewald methods in net-charged systems - Use of a FFT filter function with PME for rapid evaluation of electrostatics interactions for finite systems - Minimal explicit ion problem for periodic systems- 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 - Calculation of pK of acids groups using Free Energy Perturbation and PME corrections.- Development of improved integration techniques for molecular dynamics - Development of flexible MD techniques that remove high frequency degrees of freedom - Development of a non-reversible RESPA integrator for improved molecular dynamics simulations using a multiple timestep - Evaluation of Locally Enhanced Sampling (LES) for conformational searching - New constraint integrator; rigid bodies, massless lone pairs, and others- Other method development - Development of RMS best-fit restraints; accurate forces, relative restraints - Rational drug design: shape descriptor facility for CHARMM - Development of accurate interaction energy calculations for macromolecules - Evaluation of small molecule/protein binding energy prediction methods - Development of a rapid search strategy for docking two macromolecules There has been a significant effort in improving the techniques used to model complex systems with a mixture of quantum mechanics (QM) and classical mechanics (MM). QM/MM methods offer the possibility of treating a region of interest within a biological system quantum mechanically thereby allowing the accurate representation of bond breaking, formation, and electron transfer while also including important structural and charge effects from a surrounding classical region. 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 (Density Functional Theory) and graphic capabilities not available in either the current GAMESS, MOPAC, or CADPAC interfaces. Gaussian convolution (blurring) of classical partial charges has been implemented and tested. These delocalized charges reduce artifacts and improve on the double link atom methodology for treating QM/MM boundary conditions. The interface has been tested on small molecules which are often pathological cases for the single- and double-link atom methods. Although many of the parameter sets and models that are generally available are of the quality required for accurate simulation of macromolecular systems, there remains the need to weigh the relative merits of these sets for the specific types of systems studied. Ongoing projects include: - Evaluation and improvement of current state of the art DNA force fields - Evaluation of protein parameter sets - Evaluation of CVFF, MMFF (Merck), and other nonstandard force fields - Development and use of a polarizable and flexible water model - molecular dynamics, simulation, theory, molecular graphics, quantum mechanics, CHARMM