This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Allosteric sites have shown great potential for selective inhibition of particular protein targets but limited exploration. Such sites are difficult to target with small molecules because they are highly flexible; yet, fragment-based apporaches, and Tethering in particular, have shown promise in small molecule discovery at these sites. In Tethering, one screens a set of disulfide-containing monophores against an endogenous or engineered surface cysteine under reducing conditions to identify good binders even at low affinity using LC/MS. A computational approach to predict relative affinities of a library of monophores would be useful in guiding hit-to-lead SAR chemistry and in predicting the druggability of particular sites. I am developing a molecular dynamics analysis method to search for correlated motions to identify allosteric sites and allosteric networks of coupled residues. I am also developing an all-atoms, physics-based torsion-angle sampling molecular mechanics approach to predict relative binding affinities of cysteine-conjugating compounds and am studying the allosteric effects of these covalent compounds or soluble compounds that bind to the same site using molecular dynamics, free energy pertubation, and multiscale Monte Carlo methods. I plan to validate these predictions using a thermodynamic cycle of denaturation for binding and relaxation-dispersion NMR for dynamics.
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