[Show abstract][Hide abstract] ABSTRACT: Antimicrobial peptides form part of the immune system as protection against the action of external pathogens. The differences that exist between mammalian and microbial cell membrane architectures is a key aspect in the ability of these peptides to discriminate between pathogen and host cells. Given that the pathogen membrane is the non-specific target of these cationic peptides, different molecular mechanisms have been suggested to describe the rules that permit them to distinguish between pathogen and mammalian cells. In this context, and setting aside the old fashion idea that cationic peptides act through one mechanism alone, this work will provide insight into the molecular action mechanism of small antimicrobial peptides, based on molecular dynamics simulations of phospholipid bilayers that mimic different cell membrane architectures. After measuring different properties of these lipid bilayers, in the absence and presence of peptides, a four-step action mechanism was suggested on the basis of the formation of phospholipid rafts induced by the presence of these cationic peptides. Thus, this work shows how differences in the bending constants (k^b) of these lipid rafts and differences in the free energy profiles (Delta G(z)) associated with the insertion of these peptides into these lipid rafts are key aspects for explaining the action mechanism of these cationic peptides at a molecular level.
[Show abstract][Hide abstract] ABSTRACT: The synthesis, in vitro evaluation, and conformational study of penetratin and structurally related derivatives acting as antibacterial agents are reported. Among the compounds evaluated here, two methionine sulfoxide derivatives (RQIKIWFQNRRM[O]KWKK-NH2 and RQIKIFFQNRRM[O]KFKK-NH2 ) exhibited the strongest antibacterial effect in this series. In order to better understand the antimicrobial activity obtained for these peptides we performed an exhaustive conformational analysis using different approaches. Molecular dynamics simulations were performed using two different media (water and TFE/water). The results of these theoretical calculations were corroborated using experimental CD measurements. The electronic study for these peptides was carried out using molecular electrostatic potentials obtained from RHF/6-31G(d) calculations. In addition, the nonapeptide RQIRRWWQR-NH2 showed strong inhibitory action against the Gram-negative and Gram-positive bacteria tested in this study. This article is protected by copyright. All rights reserved.
Chemical Biology & Drug Design 04/2013; 82(2). DOI:10.1111/cbdd.12143 · 2.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this work, we studied how the lipid composition and ionic strength of an aqueous solution affect the mechanical properties of the lipid bilayer. The interfacial tension, the bending modulus, the Gaussian curvature modulus and the bilayer curvature energy of the lipid bilayer were studied by molecular dynamics simulation. For this purpose, the lipid bilayer was modelled as a binary symmetric lipid bilayer of DPPC (DiPalmitoylPhosphatidylCholine) and DPPS (DiPalmitoylPhosphatidylSerine) at different molar ratios of these two lipids in the absence of salt and in presence of 0.5 N NaCl in aqueous solution. The results of the simulations in absence of salt showed how an increase in the DPPS concentration of the lipid bilayer strongly affects most of its mechanical properties, including the lateral pressure across the membrane, interfacial tension, or the bending modulus of the lipid bilayer. However, in the presence of 0.5 N NaCl, the interfacial tension of the lipid bilayer becomes independent of the lipid composition (in the range of 15–70% DPPS), behavior that may have notable implications from a biological point of view, due to the contribution that this property may provide to the stability of biological membranes.
[Show abstract][Hide abstract] ABSTRACT: The synthesis, in vitro evaluation and conformational study of small-size peptides acting as antifungal agents are reported. These peptides displayed antifungal activity against human pathogenic strains including Candida albicans and Cryptococcus neoformans. Among the peptides reported here, RQWRRWWQR-NH2 exhibited the strongest activity against Cryptococcus neoformans. Our results allowed us to reduce in size these bioactive peptides from 16 to 11 and to 9 amino acid residues in total. Despite their reduction, they still maintained and even enhanced the antifungal activity detected for penetratin. A conformational and electronic structure analysis on these peptides was also performed by using molecular mechanics calculations in conjunction with Molecular Electrostatic Potentials (MEP) maps.
Letters in Drug Design & Discovery 06/2011; 8(6):562-567. DOI:10.2174/157018011795906785 · 0.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The synthesis, in vitro evaluation, and conformational study of penetratin analogues acting as antifungal agents are reported. Different peptides structurally related with penetratin were evaluated. Analogues of penetratin rich in Arg, Lys and Trp amino acids were tested. In addition, HFRWRQIKIWFQNRRM[O]KWKK-NH(2), a synthetic 20 amino acid peptide was also evaluated. These penetratin analogues displayed antifungal activity against human pathogenic strains including Candida albicans and Cryptococcus neoformans. In contrast, Tat peptide, a well-known cell penetrating peptide, did not show a significant antifungal activity against fungus tested here. We also performed a conformational study by means experimental and theoretical approaches (CD spectroscopic measurements and MD simulations). The electronic structure analysis was carried out from Molecular Electrostatic Potentials (MEP) obtained by using RHF/6-31G ab initio calculations. Our experimental and theoretical results permitted us to identify a topographical template which may provide a guide for the design of new peptides with antifungal effects.
European Journal of Medicinal Chemistry 01/2011; 46(1):370-7. DOI:10.1016/j.ejmech.2010.10.025 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The synthesis, in vitro evaluation, and conformational study of a new series of small-size peptides acting as antifungal agents are reported. In a first step of our study we performed a conformational analysis using Molecular Mechanics calculations. The electronic study was carried out using Molecular electrostatic potentials (MEPs) obtained from RHF/6-31G calculations. On the basis of the theoretical predictions three small-size peptides, RQWKKWWQWRR-NH(2), RQIRRWWQWRR-NH(2), and RQIRRWWQW-NH(2) were synthesized and tested. These peptides displayed a significant antifungal activity against human pathogenic strains including Candida albicans and Cryptococcus neoformans. Our experimental and theoretical results allow the identification of a topographical template which can serve as a guide for the design of new compounds with antifungal properties for potential therapeutic applications against these pathogenic fungi.