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
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Temple University
Schools of Arts and Sciences
United States
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Xia, Junchao; Flynn, William; Levy, Ronald M (2018) Improving Prediction Accuracy of Binding Free Energies and Poses of HIV Integrase Complexes Using the Binding Energy Distribution Analysis Method with Flattening Potentials. J Chem Inf Model 58:1356-1371
Cui, Di; Zhang, Bin W; Matubayasi, Nobuyuki et al. (2018) The Role of Interfacial Water in Protein-Ligand Binding: Insights from the Indirect Solvent Mediated Potential of Mean Force. J Chem Theory Comput 14:512-526
Zhang, Bin W; Cui, Di; Matubayasi, Nobuyuki et al. (2018) The Excess Chemical Potential of Water at the Interface with a Protein from End Point Simulations. J Phys Chem B 122:4700-4707
Deng, Nanjie; Cui, Di; Zhang, Bin W et al. (2018) Comparing alchemical and physical pathway methods for computing the absolute binding free energy of charged ligands. Phys Chem Chem Phys 20:17081-17092
Haldane, Allan; Flynn, William F; He, Peng et al. (2018) Coevolutionary Landscape of Kinase Family Proteins: Sequence Probabilities and Functional Motifs. Biophys J 114:21-31
He, Peng; Zhang, Bin W; Arasteh, Shima et al. (2018) Conformational Free Energy Changes via an Alchemical Path without Reaction Coordinates. J Phys Chem Lett 9:4428-4435
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
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
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

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