All‐atom Folding Simulations of Insulin B‐chain and its Mimetic Peptide

Insulin is a small peptide hormone that regulates blood glucose levels in higher organisms and thereby plays a central role in diabetes. Novel therapeutic efforts are currently underway to treat diabetes such as design of small synthetic peptides that can mimic effects of insulin binding to the insulin receptor, a cell‐surface glycoprotein of the the receptor tyrosine kinase superfamily. Although many mimetic peptide sequences have been discovered, and found to selectively function as agonists or antagonists, underlying mechanistic details as well as the structures of peptides remain elusive. In this work, we have studied the folding properties and structure of a peptide that mimics the B‐chain of insulin. Using atomistic simulation approaches involving enhanced sampling of peptide conformations, we characterize the folding thermodynamics of mimetic peptide and compare it against folding of the native peptide sequence, the structure for which is known. We observe that the native and mimetic peptides largely show similar folding behavior including underlying thermodynamic details, but various metastable states in each peptide differ. We predict a helical fold for mimetic sequence, similar to insulin B‐chain, and speculate that the stable conformation of mimetic peptide potentially engages receptor via a mechanism similar to the native hormone.