Folding propensity and biological activity of peptides: The effect of a single stereochemical isomerization on the conformational properties of bombinins in aqueous solution

Abstract

Folding propensities of bombinins H2 and H4, two members of amphibian bombinins H, a family of 17-20 residue alpha-helical peptides, have been investigated by means of circular dichroism (CD) measurements and molecular dynamics (MD) simulations. The two peptides, with primary structure IIGPVLGLVGSALGGLLKKI-NH2 and differing only for the configuration of the second aminoacid (an L-isoleucine in H2 and a D-alloisoleucine in H4) behave rather differently in solution. In particular both CD measurements and MD simulations indicate that bombinin H2 shows a markedly higher tendency to fold. From a careful inspection of MD trajectories it emerges that the stereochemical isomerization mutation of residue 2 to D-alloisoleucine in H4 peptide, drastically decreases its ability to form intrapeptide contacts. MD simulations also indicate that the conformational sampling in both systems derives from a subtle combination of energetic and entropic effects both involving the peptide itself and the solvent. The present results have been finally paralleled with preliminary information on bombinins H2 and H4 biological activity, i.e. interaction with membrane, supporting the hypothesis of an "already folded" conformation in water rather than interfacial folding tenet.

The role of d - allo -isoleucine in the deposition of the anti- Leishmania peptide bombinin H4 as revealed by 31 P solid-state NMR, VCD spectroscopy, and MD simulation

“…1 and H4 are in good agreement with the results of 13 C solid-state NMR (Fig. S3), CD, and FTIR studies, as they predominantly formed α-helical structures in the membrane [20,21,33].…”

“…The N-terminus was demonstrated to form part of the interaction site between the helices [32]. The folding structure of H4 was a little loose compared to that of H2 from the circular dichroism measurements and molecular dynamics (MD) simulations in aqueous solution [33]. The MD analysis illustrated that D-allo-Ile reduces the intrapeptide interactions that affect peptide folding [33].…”

Substrate specificity of a peptidyl-aminoacyl-l/d-isomerase from frog skin

“…As for biological activities, diverse findings have been made. These range from complete absence of activity in the all l -forms to subtle differences in folding propensities and activity of the two isomeric species (Kreil et al 1989; Zangger et al 2008; Mangoni et al 2000, 2006; Montecucchi et al 1981; Bozzi et al 2008). …”

The role of disulfide bonds and N‐terminus in the structural properties of hepcidins: Insights from molecular dynamics simulations

“…It is crucial to preliminarily observe that, in line with most of the investigated peptide systems, [20][21][22] the conformational transitions can be easily described by considering two eigenvectors deriving from the diagonalization of the Calpha covariance matrix, i.e., the eigenvectors showing the largest eigenvalues. These eigenvectors are typically termed as essential eigenvectors.…”