Abstract by David Kastner
Phi Kappa Phi
PKP:QM/MM Analysis of Proteolytically Stable Beta-Hairpins
We present a comprehensive analysis of the role of dehydroamino acid-induced β-hairpins in stabilizing peptides against proteolysis. Peptides such as the HIV drug Enfuvirtide offer the potential for unparalleled flexibility and medicinal specificity, but their implementation has been severely limited by a notoriously short half-life as the body degrades them in a process called proteolysis. As a result, peptide drugs require intensive and invasive dosing regimens to maintain concentrations. However, our experimental results show that the incorporation of dehydroamino acids increases proteolytic stability by up to seven-fold. In this research, we illustrate a computational hybrid method using molecular dynamics simulations, quantum mechanics calculations, and nuclear magnetic spectroscopy to explore a wide range of peptide conformations featuring the unique stabilizing properties of dehydroamino acids. The findings of this study suggest that incorporating dehydroamino acids into a peptide induces a highly folded β-hairpin that may in future be used to design next-generation peptide therapeutics with exceptional proteolytic stability.