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January - December 2011

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University of Minnesota Rochester
Center for Learning Innovation

PI: Xavier Prat-Resina

Molecular Simulation of Proton Channels: Proton Gating in Influenza M2 Protein

Proton channels are membrane bound proteins that selectively conduct protons across a cell membrane. Either according or against a concentration gradient, the mechanism by which the transfer occurs consists of the combination of water wires and titrable residues that pump a net number of protons from one side to other of the membrane. In most cases, atomistic detail of the proton transfer process will provide extremely useful information towards a better understanding of the mechanism and it may contribute to the design and control of proton channels.

One proton channel that has recently attracted attention is the M2 protein from influenza A virus, which is the target of influenza drugs amantidine and rimantidine. The M2 channel is a pH-activated and highly selective proton pump that consists of a homotetramer of a very small protein (96 residues). The mechanism by which this small channel can selectively pump protons vs. other ions is still not clear.

In order to build a realistic computational model to study the reaction mechanism of such process, one needs to take into account the flexibility of the tetramer bundle at a given temperature, the short and long range interactions between charged residues, as well as the forming and breaking of chemical bonds during the proton pump process. Such atomistic model consists of a reactive core treated with quantum mechanics (QM) linked to a coarser description of atoms with molecular mechanics (MM) and finally embedded in a continuum electrostatic field to simulate the low dielectric medium of the phospholipidic membrane. These researchers explore the configuration space of such model by molecular dynamics. Forcing the system to transfer a net charge across the channel allows us to compute the potential of mean force of the proton transport process and obtain a reliable estimation of its energetics.

Group Member

Nicole M. Herman, Undergraduate Student