Molecular Mechanisms of Ion Selectivity in Membrane Proteins: Ion Channels and Transporters

Abstract

The mechanism of ion binding to membrane proteins and subsequent ion regulation of protein function is a subject that has fascinated scientists for a long time. Although the implications and applications of selective ion binding are many, ranging from management of cell volume to proper electric signaling upon subsequent transport across cellular membranes to being integral part of new nano-materials, our understanding of the underlying complex thermodynamics of ion binding and subsequent permeation across cellular membranes is very limited. Recent progress in structural studies of secondary amino-acid transporters provides us with a unique opportunity to address molecular mechanism of the cation selectivity in the protein with available high-resolution crystal structure and confirmed Na+/K+ or K+/Na+ selectivity. Combined results of our studies on K-selective channels (KcsA and MthK), non-selective channels (NaK) and Na+-coupled secondary transporters will be presented. A combination of the free energy simulations with classical and polarizable force-fields as well as recently developed QM/MM FEP protocol was used for evaluation of different factors in the observed selectivity in protein sites. Atomistics simulations blazed the trail for the development of an analytical theory than allows quantification of ion selectivity within a reduced framework. In conclusion, I will present a theory to clarify the molecular determinants of ion selectivity in protein binding sites developed recently (Yu et al., PNAS 2011) that integrates our current knowledge on monovalent cation selectivity.