Hydroxide Ion Mechanism for Long‐Range Proton Pumping in the Third Proton Transfer of Bacteriorhodopsin

Abstract

In bacteriorhodopsin, representative light‐driven proton pump, five proton transfers yield vectorial active proton translocation, resulting in a proton gradient in microbes. Third proton transfer occurs from Asp96 to the Schiff base on the photocycle, which is expected to be a long‐range proton transfer via the Grotthuss mechanism through internal water molecules. Here, large‐scale quantum molecular dynamics simulations are performed for the third proton transfer, where all the atoms (∼50000 atoms) are treated quantum‐mechanically. The simulations demonstrate that two reaction paths exist along the water wire, namely, via hydronium and via hydroxide ions. The free energy analysis confirms that the path via hydroxide ions is considerably favorable and consistent with the observed lifetime of the transient water wire. Therefore, the proposed hydroxide ion mechanism, as in the first proton transfer, is responsible for the third long‐range proton transfer.

Divide-and-Conquer Linear-Scaling Quantum Chemical Computations

“…This limitation causes the system to become trapped in one of the abundant local minima and makes it impractical to access reliable physical quantities, including the free-energy landscape. The improved sampling of rare events under investigation can be addressed by combining it with the so-called enhanced sampling methods. − Among several popular enhanced sampling methods, some of our calculations ,,,− have relied on the metadynamics (MTD) technique. − The MTD method biases the dynamics by frequently depositing repulsive potentials in the space of predefined collective variables (CVs). The accumulated bias potentials become a negative value of the free-energy surface (FES) along the CV if the simulation is sufficiently long.…”

“…The performance of MTD can be improved with advanced algorithms such as well-tempered (WT) and multiple walkers (MW) variants in terms of the smooth convergence of FES and sampling efficiency, respectively. Our latest applications demonstrated that DC-based QM-MD/MTD simulations could treat chemical reactions in condensed-phase systems containing more than 10 4 atoms. − …”

“…In 2005, a cubic water box containing 216 molecules was simulated using DC-based and HF-type SE methods . The DFTB method was applied along with the DC method in the 2000s to analyze the structure, mechanics, and dynamics of protein, amylose chain, and bulk water systems. − In the last several years, more than 30 computational studies have been reported by utilizing the DCDFTBMD (or its predecessor) program introduced in section . ,− ,,,− ,,− ,,,,− …”

“…Treating large biological macromolecules has been a route to illustrate potential applicability of the DC-based approximate electronic structure methods in several pioneering studies. ,,− DC-based DFTB-MD/MTD simulations have been successfully exploited for biomolecular systems, ranging from an alanine dipeptide toy model to photoreceptor proteins with realistic surrounding environments. ,,− QM/MM simulations have become popular for biological applications, , yet the present full QM treatment no longer suffers from proper determination of the boundary between QM and MM regions. The first, second, and third proton transfer mechanisms in bacteriorhodopsin were examined using recently observed intermediate structural snapshots by experiment. ,, The system size of approximately 50,000 for the latter two simulations is worth remarking as QM-MD, while even larger simulation models containing ∼80,000 atoms were treated in the latest study on the main protease in severe acute respiratory syndrome coronavirus 2 . Besides such chemical reactions in the ground-state, the developed DC-based TDDFTB method was applied to excited-state dynamics for biochemically important molecules. , …”

Ion-transporting mechanism in microbial rhodopsins: Mini-review relating to the session 5 at the 19th International Conference on Retinal Proteins

“…These three-dimensional information with atomic resolution enabled a theoretician to analyze the proton transfer mechanism in BR using a quantum mechanics method. Dr. Junichi Ono (the fifth speaker of the session 5) focused on the proton transfer reactions in BR and revealed hydronium (H3O + ) and hydroxide (OH − ) ions are involved [39][40][41]. Namely, in the first proton transfer from the PRSB to D85, it was proposed that a transiently formed hydroxide ion pulled a proton from the PRSB [39].…”