Physical reasons for the unusual α-helix stabilization afforded by charged or neutral polar residues in alanine-rich peptides

Abstract

We have carried out conformational energy calculations on alanine-based copolymers with the sequence Ac-AAAAAXAAAA-NH2 in water, where X stands for lysine or glutamine, to identify the underlying source of stability of alanine-based polypeptides containing charged or highly soluble polar residues in the absence of charge-charge interactions. The results indicate that ionizable or neutral polar residues introduced into the sequence to make them soluble sequester the water away from the CO and NH groups of the backbone, thereby enabling them to form internal hydrogen bonds. This solvation effect dictates the conformational preference and, hence, modifies the conformational propensity of alanine residues. Even though we carried out simulations for specific amino acid sequences, our results provide an understanding of some of the basic principles that govern the process of folding of these short sequences independently of the kind of residues introduced to make them soluble. In addition, we have investigated through simulations the effect of the bulk dielectric constant on the conformational preferences of these peptides. Extensive conformational Monte Carlo searches on terminally blocked 10-mer and 16-mer homopolymers of alanine in the absence of salt were carried out assuming values for the dielectric constant of the solvent of 80, 40, and 2. Our simulations show a clear tendency of these oligopeptides to augment the ␣-helix content as the bulk dielectric constant of the solvent is lowered. This behavior is due mainly to a loss of exposure of the CO and NH groups to the aqueous solvent. Experimental evidence indicates that the helical propensity of the amino acids in water shows a dramatic increase on addition of certain alcohols, such us trifluoroethanol. Our results provide a possible explanation of the mechanism by which alcohol͞water mixtures affect the free energy of helical alanine oligopeptides relative to nonhelical ones. T he ␣-helical conformation of short homopolypeptides containing only alanines is unstable in water at room temperature (1). This behavior is consistent with the value of the Zimm-Bragg parameters (2) s and determined from experiments on random copolymers (3). If charged (4) or neutral polar (5) residues are introduced into a chain of 13 alanine residues to solubilize it in water, the helix becomes stable, more so when charged residues rather than neutral polar residues are incorporated. This behavior has been attributed to desolvation of the backbone NH and CO groups of the alanines by the preferentially hydrated charged or polar groups (6) rather than to a high intrinsic tendency of alanines to form an ␣-helix. By being deprived of a high degree of hydration, the backbone NH and CO groups can form the ␣-helical hydrogen bonds.Previous experiments (4, 5) and calculations (6, 7) treated polyalanine chains containing several charged or neutral polar guest groups, e.g., three lysines or glutamines in the copolymers AAAAKAAAAKAAAAKA and AAQAAAAQAAAAQAAY, respectively, in which the helix-stab...

α-Helical stabilization by side chain shielding of backbone hydrogen bonds

“…This force field also gives values for the helix propagation and nucleation parameters for Ala measured by Yang et al (9) but in disagreement with other experimental measurements (2, 3). Our calculations show that the Arg side chain significantly stabilizes the helix state of the Fs peptide, in agreement with Williams et al (15) and Vila et al (14). However, we also find that A21 is 34% helical at 275 K, consistent with Spek et al (8) …”

“…Simulations using the modified and original force fields describe higher stability of the Fs peptide over A21. To test the hypothesis that chain desolvation might be responsible for this stabilization (14) and to provide a molecular description of the shielding, we study the coordination of water to the peptide backbone over the last 2 ns͞replica of the simulations. Fig.…”

“…Within the Lifson-Roig (10, 11) and Zimm-Bragg (12) models for the helix-coil transition, the intrinsic propensity of an amino acid to form a helix is a measure of the interactions of the amino acid with its own and nearest-neighbor amino acid backbone (11,13). Theoretical (14) and experimental studies on prenucleated synthetic peptides (15) have suggested that the high helical propensity of Ala-containing peptides is a consequence of the neighboring side chains and is an effect extrinsic to the Ala side chains. Specifically, Vila et al (14) have argued that the high helical propensity of Ala-rich peptides containing large charged side chains is stabilized by the effect of the side chains in reducing the accessibility of the peptide backbone to water.…”

“…Theoretical (14) and experimental studies on prenucleated synthetic peptides (15) have suggested that the high helical propensity of Ala-containing peptides is a consequence of the neighboring side chains and is an effect extrinsic to the Ala side chains. Specifically, Vila et al (14) have argued that the high helical propensity of Ala-rich peptides containing large charged side chains is stabilized by the effect of the side chains in reducing the accessibility of the peptide backbone to water. It has also been argued that backbone desolvation by large side chains is responsible for helix destabilization (16,17).…”

Evolution of physics‐based methodology for exploring the conformational energy landscape of proteins

“…116 The EDMC method has proven effective in finding the global energy minimum of allatom models of polypeptides consisting of up to 20 amino acid residues, 114 -120 most notably in studying the pH dependence of the conformational properties of polypeptides. 21,121,122 Our procedure to work in a space of high dimensionality and then relax back to three dimensions 123 evolved into a methodology involving deformation of the potential energy surface to eliminate unwanted minima. This deformation was based on a solution of the diffusion equation in cartesian space with a diffusion equation method, DEM.…”