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.
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.
|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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