A.M. Rodrı́guez

New small-size peptides possessing antifungal activity

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.

Characteristics of Ramachandran maps of L-alanine diamides as computed by various molecular mechanics, semiempirical and ab initio MO methods. A search for primary standard of peptide conformational stability

Abstract The optimized geometries and relative energies obtained by four force field and two semi-empirical methods were compared with ab initio results computed for formyl- L -alaninamide. Not all methods yielded the same number of minimum energy conformers. Furthermore, while the optimized geometries of the conformers found were comparable, the computed relative energies varied substantially. Also, the force field calculations produced Ramachandran maps that did not even have the appearance of the ab initio Ramachandran map. Correlating the ab initio relative energies (Δ E ) or free energy (Δ G ) with the log of relative populations, ln( p x / p γ L ), led to linear relationships from which four conformers deviated; two of them (α L and e L ) were overly destabilized and two of them (γ L and γ D ) were over-stabilized. It is suggested that, after such deviations are corrected, a primary standard may be obtained that might be useful in further investigations related to force-field parametrization as well as protein folding.

Penetratin and derivatives acting as antifungal agents

The synthesis, in vitro evaluation, and conformational study of RQIKIWFQNRRMKWKK-NH(2) (penetratin) and related derivatives acting as antifungal agents are reported. Penetratin and some of its derivatives displayed antifungal activity against the human opportunistic pathogenic standardized ATCC strains Candida albicans and Cryptococcus neoformans as well as clinical isolates of C. neoformans. Among the compounds tested, penetratin along with the nonapeptide RKWRRKWKK-NH(2) and the tetrapeptide RQKK-NH(2) exhibited significant antifungal activities against the Cryptococcus species. A comprehensive conformational analysis on the peptides reported here using three different approaches, molecular mechanics, simulated annealing and molecular dynamics simulations, was carried out. The experimental and theoretical results allow us to identify a topographical template which may provide a guide for the design of new compounds with antifungal characteristics against C. neoformans.

An ab initio exploratory study of side chain conformations for selected backbone conformations of N-acetyl-l-glutamine-N-methylamide

Abstract The backbone potential energy surface (PES) (Ramachandran map) of N-acetyl- l -glutamine-N-methylamide has been studied at a,a side-chain orientation. Side-chain PESs at selected backbone conformations (γ l and β l ) were also studied. Side-chain–backbone interactions were analyzed in terms of energy and geometry.

Side-chain conformations for selected backbone conformations of N-acetyl-L-isoleucine-N-methylamide and N-acetyl-L-nor-isoleucine-N-methylamide. An exploratory ab initio study

Abstract The Ramachandran or backbone potential energy surface (PES) of N-acetyl- l -isoleucine-N-methylamide has been explored using the a,a side-chain conformation. The side-chain conformational PES were generated with fixed backbone conformations: γ l and β l . The β l side-chain PES of the isoleucine derivative was compared to that of the nor-isoleucine derivative.

Binding mechanism of RGD and its mimetics to receptor GPIIb/IIIa. A theoretical study

Abstract In order to better understand, at a sub-molecular level, the minimal structural requirements for the recognition process in the platelet aggregation inhibitory activity, a series of RGD mimetics were examined as fibrinogen receptor antagonists variants. We simulate the electronic interactions between RGD with its biological receptor in terms of smaller molecules. MeCOO− was used to mimic the side chain of deprotonated Asp and Meguanidinium group mimicked the side chain of the protonated Arg. Alternative moieties present on the RGD mimetics were also studied in this report. AM1; RHF/3-21G; B3LYP/6-31++G∗∗ in the gas phase. Also, B3LYP/6-31++G∗∗ calculations using the IPCM solvation model were carried out for all the complexes. Our results indicate that high level of theory calculations and the inclusion of solvent effects are crucial in order to obtain satisfactory of accuracy in the electronic distributions of these compounds.

An exploratory study of side-chain-backbone interaction in selected conformations of N-acetyl-L-glutamate-N-methylamide. An ab initio study

Abstract The Ramachandran map of N -acetyl- l -glutamate- N -methylamide has been explored using a, a side-chain (SC) conformation. Also, with fixed backbone (BB) conformations (γ l and β l ) the SC conformational potential energy surfaces were studied. The relative stabilities of the various conformers were analysed in terms of SC–BB interactions. The dynamic chirality of the glutamate SC was investigated and compared to that of the butyrate ion.

Structure of isolated tyrosyl-glycyl-glycine tripeptide. A comparative conformational study with peptides containing an aromatic ring

AbstractThe potential energy surface (PES) of tyrosyl-glycyl-glycine (YGG) tripeptide in solution was explored using EDMC (Electrostatically Driven Monte Carlo) and in the gas-phase by means of ab initio quantum chemical calculations. The theoretical computational analysis revealed that this tripeptide possesses a significant molecular flexibility. A C7 backbone conformation was the most energetically preferred for the central Gly residue, using both methodologies. Some new stable conformers that have not been previously reported were identified in the gas phase as well. This study points out the interplay of backbone and side-chain contributions in determining the relative stabilities of energy minima. In addition, the peptide backbone of YGG was compared with other small peptides containing aromatic side-chains (Phe-Gly-Gly and Trp-Gly-Gly). The comparison with experimental X-ray results was also satisfactory.