Ion Binding to a Mammalian Sodium/Proton Exchanger Membrane Protein from Molecular Dynamics Simulations

The Na+/H+ exchangers (NHE) are a family of proteins that regulate intracellular pH, sodium levels and cell volume, contribute to the control cycle, proliferation, migration vesicle trafficking. However, despite their physiological importance, detailed molecular-level structural information for NHE has been lacking. Although number prokaryotic structures sodium/proton antiporters known, it is not clear in how far insights from these applicable medically important mammalian homologs. Here we report molecular dynamics (MD) simulations at both atomic coarse-grained (CG) level detail based on first atomic-resolution structure NHE9. In particular, focus transporter-Na+ ion transporter-lipid interactions. Multiple protonation states model were identified through heuristic pKa calculations. equilibrium MD tested different combinations those conserved aspartic acid residue as likely ion-binding site. A second vicinity binding site was found enable transfer ions between solution Based developed microscopic picture events necessary can compare equivalent process antiporters. Because previous work suggested membrane composition critical activation cell-volume regulation, investigated interaction transporter with lipids cholesterol.