A Conformational Study of Lys-Arg-Asp-Ser and Analogs, a Series of Potent Antithrombotic Peptides. An Approach Based on Simulated Annealing and ¹H NMR

Abstract

Simulated annealing techniques were used to explore the conformational space of the potent antithrombotic peptide L.Lys-L.Arg-L Asp-L.Ser (KRDS) and of two analogs: D.Lys-L.Arg- L.Asp-L.Ser (K_DRDS), which is inactive, and L.Lys-L.Arg-L.Glu-L.Glu (KREE), which exhibits a strong biological activity. For each peptide, a set of initial conformations was generated and submitted to simulated annealing, including a heating to 1000 K followed by a cooling to 300 K. 200 resulting conformations of each compound were analyzed and classified according to the network of electrostatic interactions involving charged side chains and charged C- and N- terminal groups. A reduced number of conformational classes was obtained and conformations corresponding to predominant classes were found to be in qualitative agreement with structural parameters deduced from'H NMR spectra. A comparison between the classes of the active and non active peptide was achieved. Some conformations were found to be specific of active peptides.