Unraveling the mechanism of proton translocation in the extracellular half‐channel of bacteriorhodopsin

Abstract

Bacteriorhodopsin, a light activated protein that creates a proton gradient in halobacteria, has long served as a simple model of proton pumps. Within bacteriorhodopsin, several key sites undergo protonation changes during the photocycle, moving protons from the higher pH cytoplasm to the lower pH extracellular side. The mechanism underlying the long-range proton translocation between the central (the retinal Schiff base SB216, D85, and D212) and exit clusters (E194 and E204) remains elusive. To obtain a dynamic view of the key factors controlling proton translocation, a systematic study using molecular dynamics simulation was performed for eight bacteriorhodopsin models varying in retinal isomer and protonation states of the SB216, D85, D212, and E204. The side-chain orientation of R82 is determined primarily by the protonation states of the residues in the EC. The side-chain reorientation of R82 modulates the hydrogen-bond network and consequently possible pathways of proton transfer. Quantum mechanical intrinsic reaction coordinate calculations of proton-transfer in the methyl guanidinium-hydronium-hydroxide model system show that proton transfer via a guanidinium group requires an initial geometry permitting proton donation and acceptance by the same amine. In all the bacteriorhodopsin models, R82 can form proton wires with both the CC and the EC connected by the same amine. Alternatively, rare proton wires for proton transfer from the CC to the EC without involving R82 were found in an O' state where the proton on D85 is transferred to D212.

Analysis of proton wires in the enzyme active site suggests a mechanism of c‐di‐GMP hydrolysis by the EAL domain phosphodiesterases

“…From an energetic point of view, water molecules strongly assist the proton transfer between molecular groups; therefore, we obtain here low energy barriers at all stages preceding the bond cleavage. Proton transfer along water wires (or proton wires) is an essential issue in studies of proteins . It was shown previously that proton transfer routes were important in simulations of the c‐GMP hydrolysis in water .…”

“…Proton transfer along water wires (or proton wires) is an essential issue in studies of proteins. [39][40][41][42][43] It was shown previously that proton transfer routes were important in simulations of the c-GMP hydrolysis in water. 19 The works of Zhang and co-authors 44-46 described a stepwise mechanism in the nucleotidyl transfer reaction in DNA polymerases including a proton transfer through a shuttle of mediated water molecules.…”

Tracing the Pathways of Waters and Protons in Photosystem II and Cytochrome c Oxidase

“…The waters in MD trajectories can be analyzed in numerous ways. For example, the distribution of the number of waters around a key residue through the trajectory or the probability that proton donor and acceptors sites will be connected via waters can be found [115]. Potential of mean force (PMF) methods allow us to determine the energy of waters or protons passing through a specified channel [116,117].…”

The Role of Proton Transport in Gating Current in a Voltage Gated Ion Channel, as Shown by Quantum Calculations

“…(3) There are other proteins that have some sections of their internal structures very similar to those of the VSD, and that are known to transmit protons, including cytochrome c [ 68 , 69 , 70 ], bacteriorhodopsin [ 71 , 72 , 73 ], and the M2 channel of the flu virus [ 74 , 75 ]. Of the latter cases, some have water, unlike the VSD amino acid triad that can transmit a proton without water.…”