The goals of this research are the development of more accurate methods for molecular simulations of solvated proteins, the construction of multiscale kinetic network models which fully exploit this information, and the application of these new computational tools to forefront problems in structural biology and molecular biophysics. These problems include: (a) protein-ligand binding, both thermodynamics and kinetics;and (b) characterizing the landscapes for protein folding and functional transitions in the native state, with emphasis on mapping the diversity of pathways for folding and binding and their corresponding fluxes. These projects will build on the substantial progress made during the current grant period on the development of state-of-the-art methods for molecular simulations of proteins, and forefront applications which are best suited to investigation using all atom and multiscale kinetic network models.

Public Health Relevance

The goals of this research include the development of accurate methods for structure based drug design using innovative molecular simulations. The target systems for drug design include two human immune-deficiency virus (HIV) proteins - Reverse Transcriptase (RT) and Protease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function D Study Section (MSFD)
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Preusch, Peter C
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Rutgers University
Schools of Arts and Sciences
New Brunswick
United States
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Harris, Robert C; Deng, Nanjie; Levy, Ronald M et al. (2017) Computing conformational free energy differences in explicit solvent: An efficient thermodynamic cycle using an auxiliary potential and a free energy functional constructed from the end points. J Comput Chem 38:1198-1208
Flynn, William F; Haldane, Allan; Torbett, Bruce E et al. (2017) Inference of Epistatic Effects Leading to Entrenchment and Drug Resistance in HIV-1 Protease. Mol Biol Evol 34:1291-1306
Levy, Ronald M; Haldane, Allan; Flynn, William F (2017) Potts Hamiltonian models of protein co-variation, free energy landscapes, and evolutionary fitness. Curr Opin Struct Biol 43:55-62
Pal, Rajat Kumar; Haider, Kamran; Kaur, Divya et al. (2017) A combined treatment of hydration and dynamical effects for the modeling of host-guest binding thermodynamics: the SAMPL5 blinded challenge. J Comput Aided Mol Des 31:29-44
Levy, Ronald M; Cui, Di; Zhang, Bin W et al. (2017) Relationship between Solvation Thermodynamics from IST and DFT Perspectives. J Phys Chem B 121:3825-3841
Deng, Nanjie; Flynn, William F; Xia, Junchao et al. (2016) Large scale free energy calculations for blind predictions of protein-ligand binding: the D3R Grand Challenge 2015. J Comput Aided Mol Des 30:743-751
Haldane, Allan; Flynn, William F; He, Peng et al. (2016) Structural propensities of kinase family proteins from a Potts model of residue co-variation. Protein Sci 25:1378-84
Levy, Ronald M (2016) Recollection. Protein Sci 25:9-11
Wickstrom, Lauren; Deng, Nanjie; He, Peng et al. (2016) Parameterization of an effective potential for protein-ligand binding from host-guest affinity data. J Mol Recognit 29:10-21
Deng, Nanjie; Hoyte, Ashley; Mansour, Yara E et al. (2016) Allosteric HIV-1 integrase inhibitors promote aberrant protein multimerization by directly mediating inter-subunit interactions: Structural and thermodynamic modeling studies. Protein Sci 25:1911-1917

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