Comparative Study of the Mechanical Unfolding Pathways of α- and β‑Peptides

Using molecular simulations, we analyze the unfolding pathways of various peptides. We compare the mechanical unfolding of a β-alanine’s octamer (β-HAla₈) and an α-alanine’s decamer (α-Ala₁₀). Using force-probe molecular-dynamics simulations, to induce unfolding, we show that the 3₁₄-helix formed by β-HAla₈ is mechanically more stable than the α-helix formed by α-Ala₁₀, although both structures are stabilized by six hydrogen bonds. Additionally, computations of the potential of mean force validate this result and show that also the thermal stability of the 3₁₄-helix is higher. It is demonstrated that β-HAla₈ unfolds in a two-step fashion with a stable intermediate. This is contrasted with the known single-step scenario of the unfolding of α-Ala₁₀. Furthermore, we present a study of the chain-length dependence of the mechanical unfolding pathway of the 3₁₄-helix. The calculation of the dynamic strength for oligomers with chain lengths ranging from 6 to 18 monomers shows that the unfolding pathway of helices with an integer and noninteger number of turns has <i>m</i> + 1 and <i>m</i> energy barriers, respectively, with <i>m</i> being the number of complete turns. The additional barrier for helices with an integer number of turns is shown to be related to the breaking of the N-terminus’ hydrogen bond

Determining Factors for the Unfolding Pathway of Peptides, Peptoids, and Peptidic Foldamers

We present a study of the mechanical unfolding pathway of five different oligomers (α-peptide, β-peptide, δ-aromatic-peptides, α/γ-peptides, and β-peptoids), adopting stable helix conformations. Using force-probe molecular dynamics, we identify the determining structural factors for the unfolding pathways and reveal the interplay between the hydrogen bond strength and the backbone rigidity in the stabilization of their helix conformations. On the basis of their behavior, we classify the oligomers in four groups and deduce a set of rules for the prediction of the unfolding pathways of small foldamers