Abstract

The goals of this research are the development of more accurate methods for molecular simulations ofsolvated proteins, the construction of multiscale kinetic network models which fully exploit this information, andthe application of these new computational tools to forefront problems in structural biology and molecularbiophysics. 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 onmapping the diversity of pathways for folding and binding and their corresponding fluxes. We will continue ourproductive collaboration with the Arnold Group on the design of inhibitors to HIV R; and pursue newcollaborations we have started with the Kalodimos group on the recognition of signal sequence peptides uponbinding by translocase, and with the Gilson group on the computational framework for modeling bindingaffinities of host-guest systems. These projects will build on the substantial progress made during the currentgrant period on the development of state-of-the-art methods for molecular simulations using all atom andmultiscale kinetic network models.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM030580-33
Application #
8826257
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Preusch, Peter C
Project Start
1982-06-01
Project End
2015-08-31
Budget Start
2014-01-01
Budget End
2014-08-31
Support Year
33
Fiscal Year
2013
Total Cost
$255,560
Indirect Cost
$90,948

  Institution

Name
Temple University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122

  Publications

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

Showing the most recent 10 out of 105 publications