Abstract
Membrane-bound proteins that change protonation during function use specific protein groups to bind and transfer protons. Knowledge of the identity of the proton-binding groups is of paramount importance to decipher the reaction mechanism of the protein, and protonation states of prominent are studied extensively using experimental and computational approaches. Analyses of model transporters and receptors from different organisms, and with widely different biological functions, indicate common structure-sequence motifs at internal proton-binding sites. Proton-binding dynamic hydrogen-bond networks that are exposed to the bulk might provide alternative proton-binding sites and proton-binding pathways. In this perspective article I discuss protonation coupling and proton binding at internal and external carboxylate sites of proteins that use proton transfer for function. An inter-helical carboxylate-hydroxyl hydrogen-bond motif is present at functionally important sites of membrane proteins from archaea to the brain. External carboxylate-containing H-bond clusters are observed at putative proton-binding sites of protonation-coupled model proteins, raising the question of similar functionality in spike protein S.
Highlights
Proton transfer reactions are fundamental to cells from all branches of life
From graph-based analyses we discovered that titratable groups can participate in H-bond clusters that tend to have three-fold compositional symmetry when SARS-CoV-2 protein S is closed (Karathanou et al, 2020)
Proteins across all branches of life rely on proton binding and proton transfer to exert their biological function
Summary
Proton transfer reactions are fundamental to cells from all branches of life. Among proteins that use proton binding and proton transfer for biological function, one of the best studied is bacteriorhodopsin, a small light-driven proton pump of the halophile archaeon Halobacterium salinarium. Examples discussed here suggest that internal carboxylates used by membrane proteins for proton binding might be part of common inter-helical H-bond motifs; this could guide studies of other, more complex proteins for which proton-binding groups are yet to be identified.
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