Concerted movement in pH-dependent gating of FocA from molecular dynamics simulations.

FocA, a member of the formate-nitrite transporter (FNT) family, transports formate and nitrite across biological membranes in cellular organisms. The export and uptake of formate in bacteria are both mediated by FocA, which undergoes a pH-dependent functional switch. Recently, the crystal structures of Escherichia coli FocA (EcFocA), Vibrio cholerae FocA (VcFocA), and Salmonella typhimurium FocA (StFocA) were reported. We performed molecular dynamics (MD) on StFocA and EcFocA with different states of His209 (protonated and unprotonated), representing different pH conditions of FocA. The N-terminal helix in each protomer of StFocA covers and blocks the formate channel. At neutral or high pH (MD simulations with unprotonated His209), the concerted movement of the N-terminal helices of pairs of protomers of StFocA opens its formate channel. At low pH (MD simulations with protonated His209), protonated His209 interacts tightly with its neighboring residue Asn262, and the channel becomes narrower, so that the formate can hardly pass through the channel. We obtained similar results for EcFocA. Our study shows that pairs of protomers of FocA move in a concerted way to achieve its pH-dependent gating function, which provides information on the dynamics of the gating mechanism of FNT proteins and aquaporins.