Computational Studies Show How the H463R Mutation Turns hKv1.5 into an Inactivation State.

Abstract

The KCNA5 gene provides the code for the α-subunit of the potassium channel Kv1.5. The genetic variant H463R in the Kv1.5 channel has been reported to cause a functional loss in atrial fibrillation (AF) patients. Understanding the mutations at a molecular level is key to developing improved therapeutics concerning cardiac hKv1.5 and hKv1.4 channels. Molecular dynamics and umbrella sampling free energy simulations are an effective tool to understand the mutation's effect on ion conduction, which we have employed and found that the hKv1.5[H463R] mutation imposes an energy barrier on the ion conduction pathway compared to the wild-type channel's ion free energy and pore structure. These results imply that the arginine mutation associated with the AF disease in particular modulates the inactivation process of hKv1.5. Kv1.4, encoded by the KCNA4 gene, is also present in the heart. Therefore, we considered simulation studies of the equivalent H507R mutation in the hKv1.4 channel and found that the mutation slightly reduces the ion conduction barrier in the ion conduction pathway, making it insignificant.