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.
|Small, Meagan C; Aytenfisu, Asaminew H; Lin, Fang-Yu et al. (2017) Drude polarizable force field for aliphatic ketones and aldehydes, and their associated acyclic carbohydrates. J Comput Aided Mol Des 31:349-363|
|Huang, Jing; Rauscher, Sarah; Nawrocki, Grzegorz et al. (2017) CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat Methods 14:71-73|
|Huang, Jing; Simmonett, Andrew C; Pickard 4th, Frank C et al. (2017) Mapping the Drude polarizable force field onto a multipole and induced dipole model. J Chem Phys 147:161702|
|Jo, Sunhwan; Cheng, Xi; Lee, Jumin et al. (2017) CHARMM-GUI 10 years for biomolecular modeling and simulation. J Comput Chem 38:1114-1124|
|Huang, Jing; MacKerell Jr, Alexander D (2017) Force field development and simulations of intrinsically disordered proteins. Curr Opin Struct Biol 48:40-48|
|Li, Hui; Chowdhary, Janamejaya; Huang, Lei et al. (2017) Drude Polarizable Force Field for Molecular Dynamics Simulations of Saturated and Unsaturated Zwitterionic Lipids. J Chem Theory Comput 13:4535-4552|
|Huang, Jing; Mei, Ye; König, Gerhard et al. (2017) An Estimation of Hybrid Quantum Mechanical Molecular Mechanical Polarization Energies for Small Molecules Using Polarizable Force-Field Approaches. J Chem Theory Comput 13:679-695|
|Klontz, Erik H; Tomich, Adam D; Günther, Sebastian et al. (2017) Structure and Dynamics of FosA-Mediated Fosfomycin Resistance in Klebsiella pneumoniae and Escherichia coli. Antimicrob Agents Chemother 61:|
|Lin, Fang-Yu; MacKerell Jr, Alexander D (2017) Do Halogen-Hydrogen Bond Donor Interactions Dominate the Favorable Contribution of Halogens to Ligand-Protein Binding? J Phys Chem B 121:6813-6821|
|Gates, Zachary P; Baxa, Michael C; Yu, Wookyung et al. (2017) Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core. Proc Natl Acad Sci U S A 114:2241-2246|
Showing the most recent 10 out of 72 publications