Exploring the free energy landscape of a model β-hairpin peptide and its isoform

Secondary structural transitions from α-helix to β-sheet conformations are observed in several misfolding diseases including Alzheimer's and Parkinson's. Determining factors contributing favorably to the formation of each of these secondary structures is therefore essential to better understand these disease states. β-hairpin peptides form basic components of anti-parallel β-sheets and are suitable model systems for characterizing the fundamental forces stabilizing β-sheets in fibrillar structures. In this study, we explore the free energy landscape of the model β-hairpin peptide GB1 and its E2 isoform that preferentially adopts α-helical conformations at ambient conditions. Umbrella sampling simulations using all-atom models and explicit solvent are performed over a large range of end-to-end distances. Our results show the strong preference of GB1 and the E2 isoform for β-hairpin and α-helical conformations, respectively, consistent with previous studies. We show that the unfolded states of GB1 are largely populated by misfolded β-hairpin structures which differ from each other in the position of the β-turn. We discuss the energetic factors contributing favorably to the formation of α-helix and β-hairpin conformations in these peptides and highlight the energetic role of hydrogen bonds and non-bonded interactions.