Siri C. van Keulen, Eleonora Gianti, Vincenzo Carnevale, Michael L. Klein, Ursula Rothlisberger, and Lucie Delemotte (2017)
Contributed by Dries Van Rompaey
Voltage gated proton channels are membrane channels that are are regulated by both the pH gradient and the voltage. In most cases these channels only open when the electrochemical proton gradient is outwards, functioning as a passive acid extrusion mechanism. They have an exquisite selectivity for protons, prompting Delemotte and coworkers to investigate the mechanism of proton transport and the origin of this selectivity.
The mechanism for proton transport was explored using an integrative approach, combining classical simulations with QM/MM. Three separate cation binding sites can be observed in the channel, each consisting of a pair of negatively charged residues. QM/MM simulations were used to examine binding and unbinding of the proton, while conformational rearrangements were sampled using classical simulation. In contrast to the classic Grotthus mechanism, where the proton is transported through a water wire by subsequent bond formation and bond breaking, simulations indicated that the proton may traverse the channel by jumping between the acidic residues, assisted by a water molecule. As shown by classical MD, structural rearrangements occur upon proton binding, orienting the residues for the next proton jump, allowing for the proton to move through the channel. This integrative modelling study provides an interesting and novel mechanism for the transfer of a proton across a membrane. It will be interesting to see where future work on this channel leads.
Contributed by Dries Van Rompaey
Voltage gated proton channels are membrane channels that are are regulated by both the pH gradient and the voltage. In most cases these channels only open when the electrochemical proton gradient is outwards, functioning as a passive acid extrusion mechanism. They have an exquisite selectivity for protons, prompting Delemotte and coworkers to investigate the mechanism of proton transport and the origin of this selectivity.
The mechanism for proton transport was explored using an integrative approach, combining classical simulations with QM/MM. Three separate cation binding sites can be observed in the channel, each consisting of a pair of negatively charged residues. QM/MM simulations were used to examine binding and unbinding of the proton, while conformational rearrangements were sampled using classical simulation. In contrast to the classic Grotthus mechanism, where the proton is transported through a water wire by subsequent bond formation and bond breaking, simulations indicated that the proton may traverse the channel by jumping between the acidic residues, assisted by a water molecule. As shown by classical MD, structural rearrangements occur upon proton binding, orienting the residues for the next proton jump, allowing for the proton to move through the channel. This integrative modelling study provides an interesting and novel mechanism for the transfer of a proton across a membrane. It will be interesting to see where future work on this channel leads.
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