GNEIMO: Generalized Internal Coordinate Molecular Dynamics Methods

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DESCRIPTION (provided by applicant): Molecular dynamics (MD) simulations is a powerful computational tool in structural biology, widely used for understanding conformational changes in proteins, and folding of peptides. However MD simulations using Cartesian dynamics model is limited by the total simulation time scale being in tens of nanoseconds for large proteins. Biological processes on the other hand need microseconds of simulation time. Internal Coordinate Molecular Dynamics (ICMD) algorithms have been developed to enable larger simulation time-steps and they show great promise in long time scale simulations. Despite their promise, ICMD techniques have made little progress due in large part to the additional mathematical complexity of internal coordinate models. We propose to address and solve the key bottleneck problems with ICMD algorithms. We propose to develop, validate Generalized NEIMO (GNEIMO) ICMD methods that allow freezing of only bond lengths, bond angle and bond lengths and use of ICMD methods for wider conformational search using model coarsening strategies. We also propose to characterize the performance of ICMD algorithms for the applications such as 1) maintaining the native protein structure, 2) refinement of a near native homology structural models, 3) folding of alpha helical and beta hairpin peptides and 4) conformations changes in small proteins. Together, the various studies within this project will provide algorithms and a roadmap for the effective use of ICMD. We will lay the basis for integration of these algorithms with the widely used MD software package NAMD for wider dissemination.