Search

The free energy profiles for proton transfer along the oriented water file inside the gramicidin A channel were calculated. An original implementation of the rigid-body molecular dynamics method was used for describing the peptide groups of the channel and outer water molecules. The inner water wire was simulated using the PM6 force field parameters, which adequately describe the formation and cleavage of chemical and hydrogen bonds in water molecules. Different mechanisms of proton transfer through the gramicidin A channel were considered, namely, proton H+ translocation, transfer of the anion defect OH−, and reorientation of the water file inside the channel. To facilitate parallel calculations of trajectories, the reaction coordinate was divided into segments, and the results were combined by the weighted histogram analysis method. The first two processes, H+ and OH− transfers, were shown to be barrierless. Only the stage of reorientation of the water file inside the channel has an energy barrier.

We describe a new implementation of the molecular dynamics method aimed at simulation of the properties of biomolecular systems in which chemical reactions are possible. The quantum mechanical/molecular mechanical method based on the effective fragment potential theory is used for calculating the energies and forces along trajectories. Due to specific features of the effective fragment theory, the behavior of the molecular mechanical subsystem is described by rigid body dynamics. The method has been applied to simulation of proton transfer along the chain of water molecules inside the gramicidin channel.

The results of potential of mean force (PMF) calculations for the distinct stages of proton conduction through the gramicidin A channel, including proton migration, reorientation of the water file and negative ion defect migration, are presented. The negative ion defect migration mechanism was hypothesized in experimental studies but was not considered previously in molecular dynamics simulations. The model system consisted of the peptide chains constructed on the base of the structure PDBID:1JNO, the inner file of nine water molecules and external clusters of water molecules placed at both ends of the channel. Potential energy functions were computed with the CHARMM/PM6/TIP3P parameters. The results obtained for proton migration and water file reorientation are basically consistent with those reported previously by Pomes and Roux (Biophys J 82:2304, 2002) within the similar approach. For the newly considered mechanism of negative ion defect migration from the channel center to the end of the water file we obtain the energy 3.8 kcal mol(-1) which is not considerably different from the activation energy of water reorientation, 5.4 kcal mol(-1). Therefore this mechanism may principally compete for the rate-limiting step in proton conduction in gramicidin.