Rekindle therapeutic strategies for long QT syndrome from gain of function (IKr) mutations in hERG.

Abstract

The hERG (human ether-a-go-go) potassium channels are widely known for regulating the repolarisation phase in the cardiac action potential. As such, more than 200 putative disease-causing both loss- and gain-of-function mutations have been identified in these channels that are primarily attributed to the cause of Long (LQT) and Short QT (SQT) syndrome, respectively, leading to sudden death. Interestingly, all LQT-mutations reduce IKr current magnitude whereas SQT-mutations enhance hERG current. Additionally, previous studies attribute the highly dynamic nature of selectivity filter (SF) in this channel to the flickering conductance of hERG. In this work, we unearth the unique signatures that characterize the conformational dynamics and stability of the SF in an active (open) state by using molecular dynamics simulations. Here, we exploit the abnormality of attenuated inactivation of SF by SQT mutations to obtain more significant insights into the enhanced activated state and subsequently design novel therapeutics that mimics and promote the hERG activation to counteract the reduced current in LQTS. We have systematically compared the conformational heterogeneity and physicochemical interactions between the wild-type protein and SQT mutants (S631A, N588K). We demonstrate significant population shift and redistribution in the hydrogen bonded network involving the SF and S5-P region that drives the inactivation attenuation in SQT mutants. Thus, our study reveals a pattern of interactions that can be exploited to modulate the behaviour of the channel and that consequently will guide and support parallel experiments aiming to improve IKr activators.