Atomic Insights into the pH-Induced Activation of Channels and Transporters

Abstract

Many transmembrane proteins perform functions by utilizing pH-dependent conformational dynamics. However, detailed mechanisms are often elusive due to the challenge in experimentally resolving proton positions and structural details and the inability of conventional molecular dynamics simulations to couple dynamics with proton titration. In this talk I will discuss the application of state-of-the-art continuous constant pH molecular dynamics (CpHMD) to elucidate the conformational activation of Escherichia coli sodium-proton antiporter NhaA and M2 proton channel of influenza virus. As to NhaA, our study revealed the identities of proton carriers and mechanism of sodium-proton exchange. With regards to the M2 channel, simulations revealed the pH-dependent transition from the closed to open channel and provided free energy of channel opening coupled to the stepwise titration of a histidine tetrad. These studies demonstrate CpHMD is a powerful tool to obtain previously unattainable conformational details and thermodynamic information for proton-coupled channels and transporters.