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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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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