Biomolecular Modeling of neuroendocrine hormones in aqueous and physiological solutions

M.C. DONNAMARIA; M. PAULINO ZUNINI; S.N. MONACHESI; R.CARRARO; Z. CATALDI; F.LAGE

Rosario, Argentina

Congreso; XXV Reunion Anual de la Sociedad Argentina de Biofisica ,; 2006

Sociedad Argentina de Biofisica

Among the biomolecular modeling tools, the molecular dynamics simulation (MD) has proved to be a powerful technique to predict properties of molecular systems in solution. In this work, by means of MD we investigate the hydration properties in aqueous and in physiological solutions of Exendin-4 (EX4) and Glucagon like peptide-1, GLP-1. Although (EX4) is a venom, first isolated from the Gila monster salivary secretions, it is a potent agonist for the GLP-1 mammalian receptor. The interest in studying these little neuroendocrine hormones of 39 and 30 aminoacids, is because of the importance of their glucoregulatory action, for which, the both peptides become potential therapeutic agents in the diabetes and obesity control. Ex4 displays greater than 50 % sequence identity to GLP-1, and unlike GLP-1, has demonstrated to have prolonged duration of action. The MD simulations (GROMOS 96 package) are performed at constant pressure and temperature at normal conditions (P= 1bar,T= 300K) in 3ns, in aqueous and physiological solutions. In aqueous solutions the SPC/E model is used, with null electric screening (k=0). For physiological solutions two methodologies are considered, a) with reaction field (RF) with electric screening, k=0,8 (inverse of Debye length value) and, b) with monovalent counterions (CI) placed at substituted water positions, at physiological density conditions. From a) and b) results of DM, conformational and mobility preferences of both biopeptides are shown. The flexibility values (assessed by measurement of the conformational drifts, as given by the C-a, atom mean-square deviation –RSMD-from the initial structures), the mean conformations and the gyrus radii of the proteins, show that the biopeptides have alfa helical state in both aqueous and physiological solutions (in agreement with experimental evidence). This fact, corroborated by statistics of the internal hydrogen bonds, is more sticking in GLP-1, and in physiological solution, as given by the two considered models RF and CI. This current work also brings interesting data in comparing methodologies for the treatment of biosystems in aqueous and physiological solutions.a, atom mean-square deviation –RSMD-from the initial structures), the mean conformations and the gyrus radii of the proteins, show that the biopeptides have alfa helical state in both aqueous and physiological solutions (in agreement with experimental evidence). This fact, corroborated by statistics of the internal hydrogen bonds, is more sticking in GLP-1, and in physiological solution, as given by the two considered models RF and CI. This current work also brings interesting data in comparing methodologies for the treatment of biosystems in aqueous and physiological solutions. MCD is a Member of Comision de Investigaciones Cientificas de la Provincia de Buenos Aires-CIC, Argentina; MPZ and RC are scientist and PhD applicant, respectively of UDELAR, Uruguay; SNM is a PhD applicant of FCE-UNLP, Argentina, ZC and FL are Professors of LIEMA,Fi-UBA, Argentina. Authors gratefully acknowledge a bilateral cooperation agreement from CIC. MCD and SNM thank support of CONICET,CIC,UNLP. MCD also thanks a research personal CIC subsidy.