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The pH-Dependent Conformational States of Kyotorphin: A Constant-pH Molecular Dynamics Study

Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal

Correspondence: Address reprint requests to António M. Baptista, Instituto de Tecnologia Química e Biológica, Av. da República, EAN, Apartado 127, 2781-901 Oeiras, Portugal. Tel.: 351-214469619; Fax: 351-214411277; E-mail: baptista{at}itqb.unl.pt.

An extensive conformational study of the analgesic dipeptide kyotorphin (L-Tyr-L-Arg) at different pH values was performed using a constant-pH molecular dynamics method. This dipeptide showed a remarkable pH-dependent conformational variety. The protonation of the N-terminal amine was identified as a key element in the transition between the more extended and the more packed conformational states, as monitored by the dihedral angle defined by the atoms 1Cß-1C-2C-2Cß. The principal-component analysis of kyotorphin identified two major conformational populations (the extended trans and the packed cis) together with conformations that occur exclusively at extreme pH values. Other, less stable conformations were also identified, which help us to understand the transitions between the predominant populations. The fitting of kyotorphin's conformational space to the structure of morphine resulted in a set of conformers that were able to fulfill most of the constraints for the µ-receptor. These results suggest that there may be strong similarities between the kyotorphin receptor and the structural family of opioid receptors.