Mechanism Of Ion-ion And Ion-substrate Coupling In Secondary Amino-acid Transporters

Abstract

The x-ray structures of LeuT and Glt, bacterial homologues of Na+/Cl--dependent amino-acid transporters, provides a great opportunity to better understand the molecular basis of monovalent cation. Both proteins possess ion-binding sites selective for Na+ over K+ and Li+. Extensive QM/MM minimization combined with all-atom free energy molecular dynamics simulations of the LeuT and Glt transporters embedded in an explicit membrane are performed at different temperatures and various occupancy states of the binding sites to dissect the molecular mechanism of ion selectivity, coupling between co-transporter substrate and ions occupying binding sites. In this work, we demonstrate that there is a collective effect of multiple binding sites on a total selectivity for Na+ over Li+ both in LeuT and Glt. We also will discuss functional roles of different ion binding sites in the transport cycle. The role of local connectivity, site rigidity, atomic polarization and partial charge transfer in monovalent cation selectivity is discussed.