This proposal requests support for an ongoing collaboration among three faculty members, aimed at the development of molecular simulation protocols to study the conformations and energetics of both native and non-native states of peptides and proteins, and to explore the details of pH- and salt-induced conformational transitions. The primary computational tools will be continuum solvent models for conformational energetics and molecular dynamics in """"""""extended"""""""" ensembles for conformational sampling. Critical tests of the continuum solvent models will concentrate on potentials of mean force for folding/unfolding transitions in helical and beta-hairpin peptides. Based on these studies, a """"""""second generation"""""""" of generalized Born solvation models will be developed, which will be incorporated into the CHARMM and Amber molecular dynamics packages. This, in turn, should allow continuum solvent models to become efficient enough to allow us to carry out constant pH simulations, in which the protonation state of amino acid sides chains is brought to equilibrium with an external bath of protons at a given pH (via a Monte Carlo procedure) at the same time that the conformational states of the system are sampled via molecular dynamics. We will accelerate sampling through """"""""replica exchange"""""""" methods, where parallel simulations at various pH values are run, and periodically swap configurations among themselves. This combination of continuum solvent ideas and more sophisticated sampling techniques should allow us to develop practical simulation tools in which the user specifies pH and salt concentration as external thermodynamic variables, in much the same way that temperature and pressure are specified currently. This will facilitate MD simulations under these more relevant biochemical conditions to be easily accessible to a wider community.
| Bharatham, Nagakumar; Finch, Kristin E; Min, Jaeki et al. (2017) Performance of a docking/molecular dynamics protocol for virtual screening of nutlin-class inhibitors of Mdmx. J Mol Graph Model 74:54-60 |
| Laricheva, Elena N; Goh, Garrett B; Dickson, Alex et al. (2015) pH-dependent transient conformational states control optical properties in cyan fluorescent protein. J Am Chem Soc 137:2892-900 |
| Zeng, Xiancheng; Mukhopadhyay, Suchetana; Brooks 3rd, Charles L (2015) Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion. Proc Natl Acad Sci U S A 112:2034-9 |
| Goh, Garrett B; Hulbert, Benjamin S; Zhou, Huiqing et al. (2014) Constant pH molecular dynamics of proteins in explicit solvent with proton tautomerism. Proteins 82:1319-31 |
| Goh, Garrett B; Laricheva, Elena N; Brooks 3rd, Charles L (2014) Uncovering pH-dependent transient states of proteins with buried ionizable residues. J Am Chem Soc 136:8496-9 |
| May, Eric R; Arora, Karunesh; Brooks 3rd, Charles L (2014) pH-induced stability switching of the bacteriophage HK97 maturation pathway. J Am Chem Soc 136:3097-107 |
| Giamba?u, George M; Luchko, Tyler; Herschlag, Daniel et al. (2014) Ion counting from explicit-solvent simulations and 3D-RISM. Biophys J 106:883-94 |
| Bharatham, Nagakumar; Bharatham, Kavitha; Shelat, Anang A et al. (2014) Ligand binding mode prediction by docking: mdm2/mdmx inhibitors as a case study. J Chem Inf Model 54:648-59 |
| Nikolova, Evgenia N; Goh, Garrett B; Brooks 3rd, Charles L et al. (2013) Characterizing the protonation state of cytosine in transient G·C Hoogsteen base pairs in duplex DNA. J Am Chem Soc 135:6766-9 |
| Goh, Garrett B; Knight, Jennifer L; Brooks 3rd, Charles L (2013) Towards Accurate Prediction of Protonation Equilibrium of Nucleic Acids. J Phys Chem Lett 4:760-766 |
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