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.

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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Temple University
Schools of Arts and Sciences
United States
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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
Harris, Robert C; Deng, Nanjie; Levy, Ronald M et al. (2016) 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 :
Zhang, Bin W; Dai, Wei; Gallicchio, Emilio et al. (2016) Simulating Replica Exchange: Markov State Models, Proposal Schemes, and the Infinite Swapping Limit. J Phys Chem B 120:8289-301
Tan, Zhiqiang; Xia, Junchao; Zhang, Bin W et al. (2016) Locally weighted histogram analysis and stochastic solution for large-scale multi-state free energy estimation. J Chem Phys 144:034107
Mentes, Ahmet; Deng, Nan-Jie; Vijayan, R S K et al. (2016) Binding Energy Distribution Analysis Method: Hamiltonian Replica Exchange with Torsional Flattening for Binding Mode Prediction and Binding Free Energy Estimation. J Chem Theory Comput 12:2459-70
Gallicchio, Emilio; Xia, Junchao; Flynn, William F et al. (2015) Asynchronous Replica Exchange Software for Grid and Heterogeneous Computing. Comput Phys Commun 196:236-246
Dai, Wei; Sengupta, Anirvan M; Levy, Ronald M (2015) First Passage Times, Lifetimes, and Relaxation Times of Unfolded Proteins. Phys Rev Lett 115:048101
Gallicchio, Emilio; Chen, Haoyuan; Chen, He et al. (2015) BEDAM binding free energy predictions for the SAMPL4 octa-acid host challenge. J Comput Aided Mol Des 29:315-25
Deng, Nanjie; Forli, Stefano; He, Peng et al. (2015) Distinguishing binders from false positives by free energy calculations: fragment screening against the flap site of HIV protease. J Phys Chem B 119:976-88
Flynn, William F; Chang, Max W; Tan, Zhiqiang et al. (2015) Deep sequencing of protease inhibitor resistant HIV patient isolates reveals patterns of correlated mutations in Gag and protease. PLoS Comput Biol 11:e1004249

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