UC San Diego

In the context of the protein folding funnel and the energy landscape theory of protein folding, this work seeks to explain the origins of functionally related conformational transitions in proteins and RNA. Several avenues of investigation were employed. First, we extend the well know C structure-based model for protein folding, such that the energy landscape has multiple competing basins.Through this extension of the model the energetics of conformational rearrangement in Adenylate Kinase were characterized. Specifically, we found several types of motion are required to explain its functionally related conformational rearrangements. The most exciting type of motion was partial unfolding, or cracking. The next approach used was a normal mode-based model where the conformational transitions are represented as motion along the lowest frequency normal modes. While the method itself was largely borrowed from earlier work, this application provided evidence of a catalytic cycle in AKE that can serve to reduce misligation. The third line of investigation explored folding of small proteins using an all-atom structure-based model. The aim of this study was to fully understand the limits of the model, such that functional transitions may now be studied with model related artifacts removed. The final line of investigation employed an all-atom model to study the folding and function of the SAM-1 riboswitch. We hypothesize that the rate limiting steps in riboswitch folding may be related to the decision point in riboswitch function. This work explicitly included the associated ligand and identified a likely mechanism for riboswitch function.