Interaction of anesthetics with open and closed conformations of a potassium channel studied via molecular dynamics and normal mode analysis

¹ The Institute of Mathematical Sciences
² Oxford University
³ University of Pennsylvania

^* To whom correspondence should be addressed. E-mail: vani{at}imsc.res.in.

Submitted on August 20, 2007
Revised on September 10, 2007
Accepted on 15 January 2008

	Abstract

A variety of experiments suggest that membrane proteins are important targets of anesthetic molecules, and that ion channels interact differently with anesthetics in their open and closed conformations. The availability of an open and a closed structural model for the KirBac1.1 potassium channel, has made it possible to perform a comparative analysis of the interactions of anesthetics with the same channel in its open and closed states. To this end, all-atom molecular dynamics simulations supplemented by normal mode analysis have been employed to probe the interactions of the inhalational anesthetic halothane with both an open and closed conformer of KirBac1.1 embedded in a lipid bilayer. Normal mode analysis on the closed and open channel, in the presence and absence of halothane, reveals that the anesthetic modulates the global as well as the local dynamics of both conformations differently. In the case of the open channel the observed reduction of flexibility of residues in the inner helices, suggests a functional modification action of anesthetics on ion channels. In this context, preferential quenching of the aromatic residue motion and modulation of global dynamics by halothane may be seen as steps towards 'potentiating' or favoring open state conformations. The present molecular dynamics simulations provide the first insights into possible specific interactions between anesthetic molecules and ion channels in different conformations.

Key Words: anesthetic mechanism, halothane, molecular dynamics simulations, normal mode analysis, potassium channel