Abstract

The goals of this research are the development of more accurate methods for molecular simulations of solvated proteins, and their application to forefront problems in structural biology and molecular biophysics. There are three specific aims of this proposal: (1) continue to improve detailed atomic models with implicit solvent for biomolecular simulations, (2) develop advanced sampling methods for biomolecular simulations based on novel implementations of replica exchange, and (3) apply these state-of-the-art effective potentials and sampling methods to key problems in structural biology: (a) ligand binding to proteins, (b) characterization of polypeptide structural ensembles and folding pathways, and (c) modeling of crystalline vs. solution environment effects on proteins at high resolution. These projects will build on the substantial progress made during the current grant period in the development of state-of-the-art effective potentials and novel sampling methods for protein simulations, and forefront applications which are best suited to investigation using all atom models.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM030580-28S1
Application #
7932626
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Preusch, Peter C
Project Start
2009-09-30
Project End
2011-07-31
Budget Start
2009-09-30
Budget End
2011-07-31
Support Year
28
Fiscal Year
2009
Total Cost
$145,261
Indirect Cost

  Institution

Name
Rutgers University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901

  Publications

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
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
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