The role of disulfide bridges in the 3-D structures of the antimicrobial peptides gomesin and protegrin-1: a molecular dynamics study

Abstract

ABSTRACT. Some antimicrobial peptides have a broad spectrum of action against many different kinds of microorganisms. Gomesin and protegrin-1 are examples of such antimicrobial peptides, and they were studied by molecular dynamics in this research. Both have a β-hairpin conformation stabilized by two disulfide bridges and are active against Gram-positive and Gram-negative bacteria, as well as fungi. In this study, the role of the disulfide bridge in the maintenance of the tertiary peptide structure of protegrin-1 and gomesin is analyzed by the structural characteristics of these peptides and two of their respective variants, gomy4 and proty4, in which the four cysteines are replaced by four tyrosine residues. The absence of disulfide bridges in gomy4 and proty4 is compensated by overall reinforcement of the original hydrogen bonds and extra attractive interactions between the aromatic rings of the tyrosine residues. The net effects on the variants with respect to the corresponding natural peptides are: i) maintenance of the original β-hairpin conformation, with great structural similarities between the mutant and the corresponding natural peptide; ii) combination of positive Φ and Ψ Ra- Role of disulfide bridges in gomesin and protegrin-1 machandran angles within the hairpin head region with a qualitative change to a combination of positive (Φ) and negative (Ψ) angles, and iii) significant increase in structural flexibility. Experimental facts about the antimicrobial activity of the gomesin and protegrin-1 variants have also been established here, in the hope that the detailed data provided in the present study may be useful for understanding the mechanism of action of these peptides.

Effect of disulfide bridges deletion on the conformation of the androctonin, polyphemusin-I, and thanatin antimicrobial peptides: molecular dynamics simulation studies

“…The same flexibility does not happen with the Arg23 significantly to the stabilization of the β-hairpin-like structure adopted by androctonin, polyphemusin-I, and thanatin in aqueous solution. This same peculiarity was observed in our previous work [25] with the simulations of gomesin and protegrin-1 in aqueous media. Tables 3, 4, and 5 summarize the results for the cross-strand HBs, together residue because, in andry4, this residue forms an HB with the Ser2 residue, as shown in Table 3.…”

“…Interestingly, both residues occupy the position where the chain starts to fold to form the typical hairpin β-strand. Moreover, in these peptides, some Φ and Ψ angles present two preferential values [25]. These remarks support the premise that such peptides exhibit more than one meta-stable conformation in aqueous solution, which may be correlated with the broad-spectrum of their antibiotic activeties.…”

“…Experimental data for gomesin [27] assert that both dihedral angles Φ and Ψ for Lys8 are positive, while both Φ and Ψ of the neighbor Gln9 are negative. The same motif was encountered in our previous simulations of gomesin [25], (Φ, Ψ) Lys8 = (+50˚, +75˚), and protegrin-1, (Φ, Ψ) Arg10 = (+55˚, +75˚) peptides. These values correspond to the maxima in the histograms of the Ramachandran angles and not to their averages.…”

“…These remarks support the premise that such peptides exhibit more than one meta-stable conformation in aqueous solution, which may be correlated with the broad-spectrum of their antibiotic activeties. Actually, the alternative conformations must reflect some flexibility of the structure, which may be responseble for increasing the interaction efficiency between the peptides and different kinds of cellular membrane [25]. The same motif was also observed in the simulations of androctonin, polyphemusin-I, and thanatin.…”

Cyclization of the Antimicrobial Peptide Gomesin with Native Chemical Ligation: Influences on Stability and Bioactivity

“…Gomesin has sequence similarity to several peptides from other organisms, including from horseshoe crabs (tachyplesin12, 13 and polyphemusin14), Androctonus australis scorpions (androctonin)15 and porcine leukocytes (protegrins) 16. Several studies have explored the structure–activity relationships of gomesin, including replacing cysteine residues with serine17 or tyrosine,18 using cysteine residues with acetamidomethyl (Acm) protecting groups,17 designing lactam monocyclic and bicyclic analogues,17 and cysteine‐free analogues 17. Some of these modifications enhanced antimicrobial activity and confirmed that the disulfide bridges are essential for maintaining the β‐hairpin structure of gomesin and its bioactivity 11…”