It is by now well understood that proteins exist as conformational ensembles under biologically relevant conditions, and it is well accepted that characterizing this conformational plasticity is critical for understanding protein function and ultimately for designing therapeutic strategies. A number of experimental methods can be used to interrogate protein dynamics, NMR being the most important in the context of this proposal, but computational simulations are generally needed to provide a detailed structural model for these experimental observations. HIV proteins have played an important role in the study of protein conformational plasticity, in the context of, for example, substrate recognition and drug resistance of HIV protease, allosteric inhibition of RT, and vaccine and small-molecule design for entry inhibitors (e.g., [138-140]). The COMP core tackles two central challenges by developing and applying computational tools for predicting (1) allosteric effects of protein-ligand or protein-protein interactions and (2) effect of PTMs on protein structure, dynamics, and interactions.
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