CONICET | Buscador de Institutos y Recursos Humanos

One of the most used tools to identify the most active sequences of a given series of peptides are molecular simulations. Docking techniques are the most used to quickly estimate the substrate-enzyme interaction energies and study. However these types of simulations have important limitations to work with peptides as ligands, manly when the dynamics of interactions are studied.Previous studies (in vitro, in silico and in vivo) performed in our laboratory have demonstrated the ability of two amaranth tetrapeptides, ALEP and VIKP, to competitively inhibit the angiotensin-converting enzyme (ACE). The objective of this work was to study the molecular mechanism of interaction of ALEP and VIKP with ACE using molecular dynamics techniques and calculate the free energy of the binding using calculations of the MM-PBSA type. In a first stage, to generate the initial peptide-enzyme complex, a molecular dynamic of ALEP and VIKP of 5 ns was performed in the presence of H2O and NaCl with periodic boundary conditions using the AMBER12 force field. This simulation was carried out with the MOE.2013 software package. Once ACE-peptide complexes were obtained, extensive molecular dynamics studies were performed to describe the dynamics of binding and binding energies in order to infer the incidence of the structure of each peptide in its antihypertensive activity. The dynamics of the complexes were carried out with the NAMD software, with CHARMM36 force field The trajectory analyzes reveal that both VIKP and ALEP orient their carboxyl end towards Zn+2, and His 383, Tyr 523, Glu 411, Glu 384 and Ala 354 residues of ACE participate in the interaction with the active site. The molecular dynamics simulations performed allowed us to reveal the molecular mechanism of ACE inhibition by ALEP and VIKP in aqueous solutions.