protonshuttling

Proton shuttling is a mechanism by which protons are transferred efficiently within a protein or between a protein and its solvent, without large energetic penalties. It relies on a network of protonatable residues and water molecules that form a continuous hydrogen-bonded pathway, allowing protons to hop along the network via successive acid–base steps.

In many enzymes, proton shuttling couples proton transfer to chemical transformations or to proton pumping across membranes. The Grotthuss-type mechanism allows rapid movement of H+ over short distances. The network is often dynamic, reshaping as the catalytic cycle progresses, and may involve residues such as histidine, aspartate, glutamate, tyrosine, and structured water.

Examples: In carbonic anhydrase, His64 acts as a transient proton shuttle, taking up a proton from the zinc-bound water and delivering it to the solvent, thereby facilitating conversion of CO2 to bicarbonate. In membrane proteins involved in respiration, such as cytochrome c oxidase, defined proton channels relay protons from the matrix to the active site and to the pumped side, coupling electron transfer to proton translocation. Bacteriorhodopsin and related photoproteins utilize proton-relay networks to move protons across membranes in response to light.

Applications: Understanding proton shuttling informs mechanistic enzymology, enzyme design, and drug development, and helps interpret pH-dependent catalysis and energy transduction processes.