MODULATING STRUCTURE AND DYNAMICS AT ALLOSTERIC SITES USING SMALL MOLECULES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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, and because binding may not be sufficient to cause the desired effect. 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 bound geometries of cysteine-conjugating compounds and am studying the allosteric effects of these covalent compounds using molecular dynamics.