Structure and dynamics properties involved with the transport of ions across lipid membrane by ion channels using molecular dynamics simulations

Abstract

Ion channels are integral membrane proteins that select and transport ions across biological membranes. They are activated by a variety of stimuli. The molecular mechanism underlying ion selectivity and gating of ion channels has been a subject of intense research since the first crystal structure of potassium channel had been published in 1998. The aim of this thesis is to investigate the structure-function relationship of two ion channels, potassium (KvAP) channel and magnesium (TmCorA) channel, using molecular modeling and molecular dynamics simulations. The first part of the thesis is a molecular dynamics (MD) study of voltage sensor domain (VSD) of KvAP channel in two functional states, Up and Down. The MD simulations of Down-conformation conducted in two different lipid types, phospholipid and non-phospholipid bilayer, revealed higher accessible water molecules at the intracellular side of the VSD core than that of the Up-conformation. The results showed a change in the shape of water-crevice of the Down conformation with respect to that of the Up structure to accommodate the charged arginines moving towards the intracellular side of the bilayer. The second part of this thesis is the investigation of the ion selectivity of TmCorA channel. MD simulations and quantum chemical calculations were carried out to explore coordination chemistry and solvation structure of Mg2+ and other cations in the selectivity filter containing the conserved Gly-Met-Asn (GMN) sequence of TmCorA. The results showed that the GMN residues act as the second shell ligands for Mg2+. The first-shell structure of Mg2+ has six water molecules in an octahedral arrangement. The removal of Mg2+ at the Divalent Cation Sensor (DCS) site caused a weaker binding of Mg2+ to the filter. Moreover, the QM/MM results revealed the stabilization energy ordered from Co3+-hex > Al3+ > Ni2+-hex, Co2+, Ni2+, Mg2+, Ca2+ > K+ > Li+ > Na+ which is consistent with the experimental selective trend of metal ions in CorA proteins supporting the selectivity property of binding with the octahedral metal complex.