Ligand binding to the voltage gated Kv1.5 potassium channel in the open state - docking and computer simulations of a homology model

¹ Uppsala University

^* To whom correspondence should be addressed. E-mail: aqvist{at}xray.bmc.uu.se.

Submitted on May 3, 2007
Revised on May 4, 2007
Accepted on 7 September 2007

	Abstract

The binding of blockers to the human voltage-gated Kv1.5 potassium ion channel is investigated using a three-step procedure consisting of homology modelling, automated docking and binding free energy calculations from molecular dynamics simulations, in combination with the linear interaction energy method. A reliable homology model of Kv1.5 is constructed using the recently published crystal structure of the Kv1.2 channel as a template. This model is expected to be significantly more accurate than earlier ones based on less similar templates. Using the 3D homology model, a series of blockers with known affinities are docked into the cavity of the ion channel and their free energies of binding are calculated. The predicted binding free energies are in very good agreement with experimental data and the binding is predicted to be mainly achieved through non-polar interactions, while the relatively small differences in the polar contribution determine the specificity. Apart from confirming the importance of residues V505, I508, V512, and V516 for ligand binding in the cavity, the results also show that A509 and P513 contribute significantly to the non-polar binding interactions. Furthermore, we find that pharmacophore models based only on optimized free ligand conformations may not necessarily capture the geometric features of ligands bound to the channel cavity. The calculations herein give a detailed structural and energetic picture of blocker binding to Kv1.5 and the present model should thus be useful for further ligand design efforts.

Key Words: Kv1.5, Potassium channel, channel blockers, ligand docking, linear interaction energy, molecular dynamics