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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Chin, Jean
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Chicago
Schools of Medicine
United States
Zip Code
Khan, Hanif M; Grauffel, Cédric; Broer, Ria et al. (2016) Improving the Force Field Description of Tyrosine-Choline Cation-π Interactions: QM Investigation of Phenol-N(Me)4(+) Interactions. J Chem Theory Comput 12:5585-5595
Huang, Jing; Lakkaraju, Sirish Kaushik; Coop, Andrew et al. (2016) Conformational Heterogeneity of Intracellular Loop 3 of the μ-opioid G-protein Coupled Receptor. J Phys Chem B 120:11897-11904
Soteras Gutiérrez, Ignacio; Lin, Fang-Yu; Vanommeslaeghe, Kenno et al. (2016) Parametrization of halogen bonds in the CHARMM general force field: Improved treatment of ligand-protein interactions. Bioorg Med Chem 24:4812-4825
Lakkaraju, Sirish Kaushik; Lemkul, Justin A; Huang, Jing et al. (2016) DIRECT-ID: An automated method to identify and quantify conformational variations--application to β2 -adrenergic GPCR. J Comput Chem 37:416-25
Lee, Jumin; Cheng, Xi; Swails, Jason M et al. (2016) CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field. J Chem Theory Comput 12:405-13
Lemkul, Justin A; Huang, Jing; Roux, Benoît et al. (2016) An Empirical Polarizable Force Field Based on the Classical Drude Oscillator Model: Development History and Recent Applications. Chem Rev 116:4983-5013
Ngo, Van; da Silva, Mauricio C; Kubillus, Maximilian et al. (2015) Quantum effects in cation interactions with first and second coordination shell ligands in metalloproteins. J Chem Theory Comput 11:4992-5001
Li, Hui; Ngo, Van; Da Silva, Mauricio Chagas et al. (2015) Representation of Ion-Protein Interactions Using the Drude Polarizable Force-Field. J Phys Chem B 119:9401-16
Lemkul, Justin A; Roux, Benoît; van der Spoel, David et al. (2015) Implementation of extended Lagrangian dynamics in GROMACS for polarizable simulations using the classical Drude oscillator model. J Comput Chem 36:1473-9
Lopes, Pedro E M; Guvench, Olgun; MacKerell Jr, Alexander D (2015) Current status of protein force fields for molecular dynamics simulations. Methods Mol Biol 1215:47-71

Showing the most recent 10 out of 57 publications