Abstract
Proton transfer reactions are one of the most fundamental processes in biochemistry. We present a simplistic approach for estimating proton transfer probabilities in a membrane protein, cytochrome c oxidase. We combine short molecular dynamics simulations at discrete protonation states with a Monte Carlo approach to exchange between those states. Requesting for a proton transfer the existence of a hydrogen-bonded connection between the two source and target residues of the exchange, restricts the acceptance of transfers to only those in which a proton-relay is possible. Together with an analysis of the hydrogen-bonded connectivity in one of the proton-conducting channels of cytochrome c oxidase, this approach gives insight into the protonation dynamics of the hydrogen-bonded networks. The connectivity and directionality of the networks are coupled to the conformation of an important protein residue in the channel, K362, rendering proton transfer in the entire channel feasible in only one of the two major conformations. Proton transport in the channel can thus be regulated by K362 not only through its possible role as a proton carrier itself, but also by allowing or preventing proton transport via water residues.
Highlights
Proton transfer is one of the most ubiquitous elementary steps in many biochemical and biophysical processes
Proton transfer is relevant in the context of electrolytic solutions, not the least because of the auto-protolysis of water molecules into hydroxide and hydronium ions
In each of the two snapshots, there are fifteen water molecules inside the K-channel which are considered as possible carriers of the excess proton
Summary
Proton transfer is one of the most ubiquitous elementary steps in many biochemical and biophysical processes. It is at the heart of acid–base-catalyzed reactions, before and after the actual bond-breaking or bond-forming step, or tautomerizations which transform a molecule in a related, yet different one with, e.g., different hydrogen bonding patterns. Via membrane proteins, is one such fundamental biochemical process. In most cases, such proton transport is highly regulated and often coupled to a reaction that provides the energy for the “pumping” of protons against a chemical gradient. Famous examples of proton pumping membrane proteins belong to the respiratory chain: respirator complexes I and II and cytochrome c oxidase (complex IV)
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