Computations based on atomistic models are playing an increasingly important role in understanding biomolecular systems. To date, these computations have typically been performed using potential functions that account for many-body polarization effects in an average way using an effective parameterization of the atomic partial charges. To overcome this limitation during the first funding period we have undertaken the development of a potential energy function for proteins and lipids that includes the explicit treatment of induced electronic polarization via the classical Drude oscillator model. The studies proposed in the present grant submission focus on completion of the optimization of parameters targeting model compounds representative of proteins and lipids followed by testing of the developed force field in macromolecular systems for which extensive experimental data exist. Small molecule based optimization in Aim 1 will target compounds representing ionization states of amino acids required for pKa calculations and optimization of the phi, psi backbone and chi sidechain parameters using di- and polypeptide quantum mechanical and experimental data. Parameters developed in Aim 1 will be tested on a series of model polypeptides with different helical, beta sheet and beta turn propensities via Hamiltonian tempering replica-exchange in explicit solvent and in simulations of high-resolution proteins both in solution and crystal environments to validate that the force field can reproduce experimentally accessible structural and dynamic properties.
Aim 3 will focus on quantitative evaluation of the ability of the force field to reproduce energetic observables including pKa shifts in selected proteins, redox potentials and electron transfer rates in rubredoxin, cooperative binding of Ca2+ to the EF-hands in calbindin D9k, and interfacial potentials of lipid monolayers and bilayers. Upon completion of the proposed study a state-of-the-art polarizable empirical force field for proteins and lipids will be available to the computational chemistry community. In addition, novel insights on the contribution of electronic polarization to a number of biological phenomena will be obtained.
The goal of this research project is to complete the development of a force field accounting explicitly for induced polarization for proteins and membranes. Such a force field will have an improved accuracy that will permit realistic computer simulations of a wide range of molecular systems that have biomedical importance. These types of computer simulations also play a critical role in the drug discovery and lead optimization.
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|Villa, Francesco; MacKerell Jr, Alexander D; Roux, Benoît et al. (2018) Classical Drude Polarizable Force Field Model for Methyl Phosphate and Its Interactions with Mg2. J Phys Chem A 122:6147-6155|
|Aleksandrov, Alexey; Lin, Fang-Yu; Roux, Benoît et al. (2018) Combining the polarizable Drude force field with a continuum electrostatic Poisson-Boltzmann implicit solvation model. J Comput Chem 39:1707-1719|
|Khan, Hanif Muhammad; MacKerell, Alexander D; Reuter, Nathalie (2018) Cation-? interactions between methylated ammonium groups and tryptophan in the CHARMM36 additive force field. J Chem Theory Comput :|
|Lin, Fang-Yu; MacKerell Jr, Alexander D (2018) Improved Modeling of Halogenated Ligand-Protein Interactions Using the Drude Polarizable and CHARMM Additive Empirical Force Fields. J Chem Inf Model :|
|Lin, Fang-Yu; MacKerell Jr, Alexander D (2018) Polarizable Empirical Force Field for Halogen-Containing Compounds Based on the Classical Drude Oscillator. J Chem Theory Comput 14:1083-1098|
|Huang, Jing; MacKerell Jr, Alexander D (2018) Force field development and simulations of intrinsically disordered proteins. Curr Opin Struct Biol 48:40-48|
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|Han, Kyungreem; Venable, Richard M; Bryant, Anne-Marie et al. (2018) Graph-Theoretic Analysis of Monomethyl Phosphate Clustering in Ionic Solutions. J Phys Chem B 122:1484-1494|
|Lin, Fang-Yu; Lopes, Pedro E M; Harder, Edward et al. (2018) Polarizable Force Field for Molecular Ions Based on the Classical Drude Oscillator. J Chem Inf Model 58:993-1004|
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