(713e) Thermodynamics of Peptide Folding in Aqueous and Membrane Environments

Understanding how proteins fold into specific three-dimensional structures is a problem of high biological significance that has been extensively probed using experimental and theoretical approaches. Many theoretical and computational techniques so far have been applied to study mechanisms of folding of small globular proteins for which experimental structures are known, but such techniques have not been extensively used to predict folded states of novel sequences. In this work, we have studied using atomistic simulations the folding thermodynamics and structures of peptides of the insulin family in aqueous and membrane environments. In aqueous conditions, we have studied the folding of a peptide that mimics the B-chain of hormone insulin, and in the membrane, we have studied the folding of the transmembrane domains of the insulin and insulin-like growth factor receptors. We observe that native and mimetic peptides largely show similar folding behavior including underlying thermodynamic details, but some metastable states in each peptide differ. We further combine data from multiple independent folding trajectories of each peptide and build a configurational network of folding pathways that is consistent with the predictions from thermodynamic analysis. We predict a largely helical fold for mimetic sequence, similar to the B-chain of insulin, and suggest that the stable conformation of the mimetic peptide potentially engages receptor via a mechanism similar to the native hormone. For the membrane peptide folding, we compare the predicted structures of receptor transmembrane domains and discuss consistency of these structural ensembles with a recent NMR study. These results combined have implications for understanding multiple roles of peptides in regulatory, signaling, and binding events at the molecular scale.