The pH-dependent conformational states of kyotorphin: a constant-pH molecular dynamics study

¹ ITQB - Univ. Nova de Lisboa

^* To whom correspondence should be addressed. E-mail: baptista{at}itqb.unl.pt.

Submitted on June 29, 2006
Revised on July 19, 2006
Accepted on 15 November 2006

	Abstract

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 1C-1C-2C-2C. 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 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.

Key Words: analgesic, dipeptide, morphine, principal component analysis