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. Loops in protein structures tend to be more flexible than regular secondary structure. This ability to rearrange is sometimes exploited in ligand binding, protein-protein interactions, and molecular recognition. This computational work will test a hypothesis frequently refered to as 'conformational selection', which postulates that conformational changes observed in these processes represent conformational substates with significant populations in the free protein. That is, ligand binding does not induce a conformational change, but rather selects a pre-existing substate of the ensemble of states populated in the native protein. Our specific focus will be flexible loops involved in sequestering ligands from solvent in alpha-beta barrel proteins (including the canonical 'TIM barrel'). The computational methods used will be molecular dynamics, using multi-temperature replica-exchange (16-64 temperatures running in parallel on individual processors) to greatly accelerate convergence. Analysis of the trajectories will identify loop conformational sub-states and their relative stabilities in the presence and absence of ligand. This data will directly test the conformational selection hypothesis, and may provide a practical method of predicting possible conformational responses to ligand binding, which is a major challenge in rational drug design.
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