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* Structural Biology and Biochemistry, Hospital for Sick Children, Toronto, Ontario, Canada, Department of Physiology, Stritch School of Medicine, Loyola University-Chicago, Maywood, Illinois, USA, and Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
Correspondence: Address reprint requests to R. Pomès, Structural Biology and Biochemistry, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. Tel.: 1-416-813-5686; Fax: 1-416-813-5022; E-mail: pomes{at}sickkids.ca.
Gramicidin is a hydrophobic peptide that assembles as a head-to-head dimer in lipid membranes to form water-filled channels selective to small monovalent cations. Two diastereoisomeric forms, respectively SS and RR, of chemically modified channels in which a dioxolane ring links the formylated N-termini of two gramicidin monomers, were shown to form ion channels. To investigate the structural basis underlying experimentally measured differences in proton conductance in the RR and SS channels, we construct atomic-resolution models of dioxolane-linked gramicidin dimers by analogy with the native dimer. A parametric description of the linker compatible with the CHARMM force field used for the peptide is derived by fitting geometry, vibrational frequencies, and energy to the results of ab initio calculations. The linker region of the modified gramicidin dimers is subjected to an extensive conformational search using high-temperature simulated annealing, and free-energy surfaces underlying the structural fluctuations of the channel backbone at 298K are computed from molecular dynamics simulations. The overall secondary structure of the ß-helical gramicidin pore is retained in both linked channels. The SS channel is found in a single conformation resembling that of the native dimer, with its peptide bonds undergoing rapid librations with respect to the channel axis. By contrast, its RR counterpart is characterized by local backbone distortions in which the two peptide bonds flanking the linker are markedly tilted in order to satisfy the pitch of the helix. In these distorted structures, each of the two carbonyl groups points either in or out of the lumen. Flipping these two peptides in and out involves thermally activated transitions, which results in four distinct conformational states at equilibrium with one another on a nanosecond time scale. This work opens the way to detailed comparative studies of structure–function relationships in biological proton ducts.
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  S. Narayan, D. L. Wyatt, D. S. Crumrine, and S. Cukierman Proton Transfer in Water Wires in Proteins: Modulation by Local Constraint and Polarity in Gramicidin A Channels Biophys. J., September 1, 2007; 93(5): 1571 - 1579. [Abstract] [Full Text] [PDF]
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