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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057513-07
Application #
6891239
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Wehrle, Janna P
Project Start
1998-05-01
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
7
Fiscal Year
2005
Total Cost
$346,444
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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
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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
Goh, Garrett B; Knight, Jennifer L; Brooks 3rd, Charles L (2013) pH-dependent dynamics of complex RNA macromolecules. J Chem Theory Comput 9:935-943
Cheatham 3rd, Thomas E; Case, David A (2013) Twenty-five years of nucleic acid simulations. Biopolymers 99:969-77

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