Ricerc@Sapienza

The Human Ether-à-go-go-Related Gene is a gene that codifies for the alpha subunit Kv11.1 of the simply denoted hERG channel. It is a voltage dependent potassium channel found prevalently in the cardiac tissue that contributes to its cell membranes repolarization regulating the heart mechanics. This is possible by the gating mechanism that modulates the transition between the open and closed states of the channel due to the membrane potential variation. Loss of function of hERG channel is associated to the Long QT Syndrome, a condition linked to sudden cardiac death caused by both genetic mutations and assumption of not specific drugs. In order to minimize the risk of producing pro-arrhythmia drugs, the Comprehensive in Vitro Proarrhythmia Assays that allow to study in a computational way this channel to understand whether candidate drugs block it in the closed state or delay its opening. What I propose in this project is to study the hERG channel with a computational approach based on Molecular Dynamics simulations that gives the possibility to explore phenomena with the correct spatial and temporal resolution allowing to connect the protein structure to its function and dynamics. In order to characterize the transition path from open to closed state and vice versa, starting from the solved open structure, at first I will produce a more realistic closed model via Steered Molecular Dynamics simulations and then I will study the gating kinetics by means of Targeted Molecular Dynamics. Finally, I will produce specific mutants of the channel to compare the physiological to the pathological path. Understanding the molecular mechanism underlying hERG channel gating, focusing on the crucial residues and their interactions, is important not only for human health but also to extract the general principles to design artificial nanopores and biosensors with higher selectivity.