Structure and mechanism of maximum stability of isolated alpha-helical protein domains at a critical length scale

Abstract

Abstract. The stability of alpha helices is important in protein folding, bioinspired materials design, and controls many biological properties under physiological and disease conditions. Here we show that a naturally favored alpha helix length of 9 to 17 amino acids exists at which the propensity towards the formation of this secondary structure is maximized. We use a combination of thermodynamical analysis, well-tempered metadynamics molecular simulation and statistical analyses of experimental alpha helix length distributions and find that the favored alpha helix length is caused by a competition between alpha helix folding, unfolding into a random coil and formation of higher-order tertiary structures. The theoretical result is suggested to be used to explain the statistical distribution of the length of alpha helices observed in natural protein structures. Our study provides mechanistic insight into fundamental controlling parameters in alpha helix structure formation and potentially other biopolymers or synthetic materials. The result advances our fundamental understanding of size effects in the stability of protein structures and may enable the design of de novo alpha-helical protein materials.

Single-molecule mechanical unfolding experiments reveal a critical length for the formation of α-helices in peptides

“…5 Understanding the basics of the formation of a-helices in proteins, as well as their stability under external stress, as constantly experienced by proteins in the turbulent environment of cells, is crucial. 7,8 Many computational studies showed that the stability of a-helices depends on the primary sequence of amino acids, the number of amino acids, as well as the environment (solvent, pH, temperature, external force, etc.). [9][10][11][12][13][14] Buehler and…”

A p7 Ion Channel-derived Peptide Inhibits Hepatitis C Virus Infection in Vitro

“…1A), which differ from p7 (5a) because of the sequence differences between viral strains. The ␣ helix is the most prevalent secondary structure in proteins (reflecting ϳ30% of each protein across the entire Protein Data Bank) and is characterized by a right-handed coil stabilized by hydrogen bonds between the backbone residues of the polypeptide chain (26,27). Peptides with a helical conformation are likely to be more stabilized than those with a random coil conformation.…”

Significance of bending restraints for the stability of helical polymer conformations

“…By cooling, helical polymers can undergo a direct structural transition from random-coil structures to helical conformations [44][45][46][47][48]. With the inclusion of nonbonded interactions, helical segments of sufficient length tend to assemble into helical bundles [49][50][51][52][53][54][55][56].…”