Extreme Stability of an Unsolvated α-Helix

Abstract

High-temperature ion mobility measurements have been performed for alpha-helical Ac-A15K+H+ and globular Ac-KA15+H+ peptides. The alpha-helical and globular conformations do not melt into random coils as the temperature is raised. Instead, both conformations survive to the point where the peptide signals vanishes due to fragmentation. This occurs at 600 K for the globular Ac-KA15+H+ peptide and at 725 K for the alpha-helical Ac-A15K+H+. For the helical Ac-A15K+H+ peptide it appears that fragmentation is triggered by disruption of the helical conformation.

Unraveling the Stability of Polypeptide Helices: Critical Role of van der Waals Interactions

“…As detailed below, we find that vdW interactions stabilize native gas-phase helical forms of alanine polypeptide by a factor of 2 in relative energy over the fully extended structure on top of the widely used and established Perdew-Burke-Ernzerhof (PBE) [25] density functional. Only the inclusion of vdW forces can fully explain the remarkable stability of chargecapped polyalanine (Ac-Ala n -LysH þ ) helices up to a temperature of % 725 K as recently observed in gas-phase experiments by Jarrold and co-workers [15]. In contrast, PBE simulations without vdW forces lead to unfolded structures at significantly lower temperatures, being in spurious agreement with solution-phase experiments [26].…”

“…While the role of interactions underpinning helical stability (vdW, hydrogen bonding, and helix termination) has been established above, the missing ingredient to connect our calculations to real experimental systems [12][13][14][15] is including temperature effects. We first turn to the freeenergy hierarchy of different structure prototypes of Ac-Ala 15 -LysH þ .…”

“…Our study reveals the crucial role that van der Waals (vdW) interactions play for the helix stability and dynamics, illustrating how entropy is significantly altered as well. We choose polyalanine as a target for our study due to its high propensity to form helical structures [11], and its widespread use as a benchmark system for peptide stability in experiment [12][13][14][15] and in theory (see, e.g., Refs. [16][17][18][19][20][21][22][23][24] and references therein).…”

“…We first turn to the freeenergy hierarchy of different structure prototypes of Ac-Ala 15 -LysH þ . This peptide remains helical in experiment up to % 725 K [15]. Let us first analyze the temperature effects on the stability of -helical AcAla 15 -LysH þ using the harmonic approximation.…”

First-Principles Models for van der Waals Interactions in Molecules and Materials: Concepts, Theory, and Applications

“…102,335−338 In a recent AIMD study, 334 it was shown that the inclusion of vdW forces can explain the notable stability of polyalanine (Ac-Ala n -LysH + ) helices up to a temperature of 725 K. 339 Figure 12 illustrates the fact that AIMD simulations at the PBE and PBE+TS levels of theory paint very different pictures of the dynamical helix structure over a wide range of temperatures. For instance, AIMD simulations at 700 K with PBE+TS give a structure that is comprised of both α and 3 10 -helical motifs with an overall helical structure that is preserved after 65 ps of simulation, whereas PBE predicts that the α-helical motifs quickly disappear within 5−7 ps, in contradiction to the experimental evidence.…”