Structure and dynamics of a proton wire: a theoretical study of H+ translocation along the single-file water chain in the gramicidin A channel

Abstract

The rapid translocation of H+ along a chain of hydrogen-bonded water molecules, or proton wire, is thought to be an important mechanism for proton permeation through transmembrane channels. Computer simulations are used to study the properties of the proton wire formed by the single-file waters in the gramicidin A channel. The model includes the polypeptidic dimer, with 22 water molecules and one excess proton. The dissociation of the water molecules is taken into account by the "polarization model" of Stillinger and co-workers. The importance of quantum effects due to the light mass of the hydrogen nuclei is examined with the use of discretized Feynman path integral molecular dynamics simulations. Results show that the presence of an excess proton in the pore orients the single-file water molecules and affects the geometry of water-water hydrogen bonding interactions. Rather than a well-defined hydronium ion OH3+ in the single-file region, the protonated species is characterized by a strong hydrogen bond resembling that of O2H5+. The quantum dispersion of protons has a small but significant effect on the equilibrium structure of the hydrogen-bonded water chain. During classical trajectories, proton transfer between consecutive water molecules is a very fast spontaneous process that takes place in the subpicosecond time scale. The translocation along extended regions of the chain takes place neither via a totally concerted mechanism in which the donor-acceptor pattern would flip over the entire chain in a single step, nor via a succession of incoherent hops between well-defined intermediates. Rather, proton transfer in the wire is a semicollective process that results from the subtle interplay of rapid hydrogen-bond length fluctuations along the water chain. These rapid structural fluctuations of the protonated single file of waters around an average position and the slow movements of the average position of the excess proton along the channel axis occur on two very different time scales. Ultimately, it is the slow reorganization of hydrogen bonds between single-file water molecules and channel backbone carbonyl groups that, by affecting the connectivity and the dynamics of the single-file water chain, also limits the translocation of the proton across the pore.

A Secondary Gate As a Mechanism for Inhibition of the M2 Proton Channel by Amantadine

“…20 We determined whether continuous water wires were formed in our simulations by identifying hydrogen bonds between water molecules in the pores. During the apo simulation ( Figure 2a-d), most of the time, the water wire was broken by both the primary and secondary gates; occasionally, it was broken by just one of them; only rarely was a continuous water wire observed.…”

Wide-dynamic-range kinetic investigations of deep proton tunnelling in proteins

“…Figure 5 shows amino acid residues with high pK a as active elements in a hypothetical proton wire. The downstream proton current is attenuated by the ~ns deep tunneling rate, ℓ , which is much slower than the ∼ps time-scale proton hopping rate, , found for transport within the water segments 25 . A shorter segment of the wire is shown in panels b and c of Fig.…”

“…Wellaligned proton wires that are composed solely of water molecules are known to be extremely efficient charge carriers that can transport an excess proton on a sub-ps timescale 25 ; however, these water structures can be unstable, especially when long distances need to be traversed 50 .…”

“…The proton wire in GFP includes amino acid components that are found in other biological systems 17 and, importantly, this wire has evolved to include a high pK a residue (Ser205) as an active transport element. Thus, the detailed experiments presented here provide insight on the structure and function of such wires as well as an opportunity to test various theoretical models that apply to PT in proteins 8,10,12,[22][23][24][25][26][27] .…”

Molecular basis of proton uptake in single and double mutants of cytochromecoxidase

“…Our previous study of functional hydration in the D channel characterized the conformational equilibrium between the 'closed' and 'open' conformations of N139, in which the side chain prevents and allows the formation of a hydrogen-bonded chain of water molecules, respectively (figures 2(a) and (b)) [11]. The conformational isomerization between the preferred closed state and the metastable open state was inferred to provide a conformational gate for proton uptake, since the presence of hydrogen bonds is a prerequisite for water-mediated proton relay [9] across the narrow bottleneck of the D channel.…”