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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Gallicchio, Emilio; Deng, Nanjie; He, Peng et al. (2014) Virtual screening of integrase inhibitors by large scale binding free energy calculations: the SAMPL4 challenge. J Comput Aided Mol Des 28:475-90
Xia, Junchao; Levy, Ronald M (2014) Molecular dynamics of the proline switch and its role in Crk signaling. J Phys Chem B 118:4535-45
Yi, Guohua; Lapelosa, Mauro; Bradley, Rachel et al. (2013) Chimeric rhinoviruses displaying MPER epitopes elicit anti-HIV neutralizing responses. PLoS One 8:e72205
Xia, Junchao; Deng, Nan-jie; Levy, Ronald M (2013) NMR relaxation in proteins with fast internal motions and slow conformational exchange: model-free framework and Markov state simulations. J Phys Chem B 117:6625-34
Levy, Ronald M; Dai, Wei; Deng, Nan-Jie et al. (2013) How long does it take to equilibrate the unfolded state of a protein? Protein Sci 22:1459-65
Wickstrom, Lauren; Gallicchio, Emilio; Levy, Ronald M (2012) The linear interaction energy method for the prediction of protein stability changes upon mutation. Proteins 80:111-25
Lapelosa, Mauro; Gallicchio, Emilio; Levy, Ronald M (2012) Conformational Transitions and Convergence of Absolute Binding Free Energy Calculations. J Chem Theory Comput 8:47-60
Tan, Zhiqiang; Gallicchio, Emilio; Lapelosa, Mauro et al. (2012) Theory of binless multi-state free energy estimation with applications to protein-ligand binding. J Chem Phys 136:144102
Gallicchio, Emilio; Levy, Ronald M (2012) Prediction of SAMPL3 host-guest affinities with the binding energy distribution analysis method (BEDAM). J Comput Aided Mol Des 26:505-16
Gallicchio, Emilio; Levy, Ronald M (2011) Advances in all atom sampling methods for modeling protein-ligand binding affinities. Curr Opin Struct Biol 21:161-6

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