The M2 protein from influenza A virus forms a pH-dependent channel which performs selective proton transport across the viral envelope1 where the transmembrane domain is a left-handed four helix bundle with a well-defined hydrophilic pore and that two conserved residues inside the pore, His-37 and Trp-41, physically occlude the C-terminal end of the pore2. In particular, His-37 plays a crucial roles in the pH-regulated proton conductance as the imidazole moiety of His-37 accepts and stores protons from water molecules in the pore.  His-37 protonation is responsible for the activation and selectivity of the channel2. We focus our research on the calculation of pKa values of the histidine-tryptophan structural motif of the M2 channel responsible for proton storage and conduction. In particular,  constrained ab initio molecular dynamics simulation is used to study a model system containing a cluster of histidine and tryptophan residues in aqueous solution in which our investigation concerns proton dissociation from the Nd position. Using the statistical mechanical method, the Pka value is determined from the free energy profile. The deprotonation of histidine in aqueous solution is used as a reference in the study of proton dissociation from a histidine-tryptophan structural motif. Furthermore, the investigation of the effects of system size and dispersion interactions for histidine systems will allow us to estimate the accuracy of our histidine-tryptophan cluster results.  References[1] cell 1992  , 69, 517.; Nature 2008  , 451, 591.; Science 2010  , 330, 505.[2] PNAS 2010  , 107, 15075.; J. Phys. Chem. C. 2010  , 114, 20856.

Proton affinity of a histidine-tryptophan structural motif from ab initio molecular dynamics

244th National Meeting (2012)

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