Next Generation Forcefield for Internal Coordinate Mechanics

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DESCRIPTION (provided by applicant): Molecular modeling using internal coordinates, rather than more traditional Cartesian approaches, is gaining recognition because of its significant computational efficiency advantages. Molsoft's ICM (Internal Coordinate Mechanics) is among the very few molecular modeling programs built from the ground up using internal coordinates. ICM is probably the only such software program with the breadth of application fields including protein structure prediction, peptide and ligand conformational analysis, protein/protein and protein/ligand docking and virtual screening. In any molecular mechanics application, the accuracy of the force-field is the foundation for successful modeling. Working in internal coordinates, in particular torsions, imposes specific requirements on the force-fields used in the simulations. Indeed, when Cartesian force-field energy is (mis)used to evaluate conformations generated in torsion space (with the covalent geometry frozen), large errors in the relative energies of energy minima as well as rotation barriers are inevitable because the Cartesian force-field parameters are optimized on structures with relaxed covalent geometry. The ECEPP05 force-field recently developed and published by Prof. Harold Scheraga's group at Cornell University represents a major step forward in the development of torsion space force-fields. Importantly, solvation parameters specifically derived to work in conjunction with other non-bonded and bonded terms were also developed and are in the late stages of publication. Phase I of this project will focus on the implementation and integration of ECEPP05 into the ICM platform. At the end of Phase I, we expect to have a release of ICM that will allow users to apply the new force-field in their protein simulations. We will further test the performance of the new force-field in loop modeling. We already have a Monte-Carlo minimization-based loop simulation protocol implemented in ICM. This protocol showed promising results in internal benchmarking, and we expect to achieve higher accuracy in this important class of polypeptide simulations using the new force-field. The long term (Phase II) goal of this proposal is to further expand ECEPP05 into a general-purpose force-field that could be applied to small molecules and in particular in docking. Other extensions will include parameters for DNA and metalloprotein modeling. PUBLIC HEALTH RELEVANCE: Molecular mechanics techniques increasingly allow in-silico simulation of essential biological processes at the atomic level. Molsoft's ICM (Internal Coordinate Mechanics) software platform is a particularly efficient modeling tool because of its use of internal variables, rather than traditional Cartesian coordinates, in the description of the molecular structure. ICM is increasingly used by researchers in various structural and computational biology projects, including computer-assisted drug discovery. The force-fields that quantitatively describe atomic interactions are at the heart of molecular mechanics modeling, and the accuracy of molecular simulation can only be as good as the underlying force-fields. Equipping structural biologists with the latest ECEPP05 force-field from Cornell University, together with its further improvements at Molsoft, will help bring molecular simulations and structure predictions to the next level of accuracy. Successful structure modeling will ultimately help improve our understanding of molecular mechanisms underlying disease and help accelerate structure-based drug discovery efforts.