True-atomic-resolution insights into the structure and functional role of linear chains and low-barrier hydrogen bonds in proteins

Borshchevskiy, Valentin; Kovalev, Kirill; Efremov, Rouslan G.; Astashkin, Roman; Bourenkov, Gleb; Bratanov, Dmitry; Balandin, Taras; Chizhov, Igor; Baeken, Christian; Gushchin, Ivan; Kuzmin, Alexander; Alekseev, Alexey; Rogachev, Andrey; Willbold, Dieter; Engelhard, Martin; Bamberg, Ernst; Büldt, Georg; Gordeliy, Valentin

doi:10.1038/s41594-022-00762-2

Cited by 31 publications

(48 citation statements)

References 98 publications

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“…Replacement of Thr46 by a valine decreased the apparent pK of Asp96 by approximately two pH units [242], which may characterize the contribution of the H-bond between Thr46 and Asp96 to the unusually high apparent pK of the latter. The photoisomerization of the retinal twists the α-helices and lets water molecules in the space between them, see the pink structure [209,218,219,[243][244][245][246]247. The pK value of Asp-96 shifts to 7.1, which allows its deprotonation and proton transfer, via a transiently formed water chain, to the Schiff base of retinal at about 10 Å, see {Luecke, 2000 #3390, 248,249].…”

Section: Is Asp Wb An Universal Trap For a Proton From Wcat?mentioning

confidence: 99%

“…However, direct tracing of intra-protein displacements of protons in energy converting enzymes and chemical models (see [199,200,[207][208][209][210][211][212][213][214][215][216][217][218][219] for reviews) showed that fast proton transfer over a distance of up to 20 Å can be mediated by water bridges, provided that the distance between the groups involved is ≤ 3.0 Å, in accordance with Eigen [200]. Thereby it does not matter that water molecules are equally poor proton acceptors (with pKb of 0.0) and proton donors (with pKa of 14.0) because protons pass water by so-called von Grotthuss mechanism [220][221][222].…”

Section: Is Asp Wb An Universal Trap For a Proton From Wcat?mentioning

confidence: 99%

“…The two proton transfer routes shown in Fig. 10A-B were reconstructed from direct electrometric tracking of flash-induced proton displacements [209,[250][251][252][253][254], kinetic IR and UV/Vis spectroscopy data [209,210,230,231,248,251,255,256], kinetic ESR measurements [238,243,245,257], and comparative structure analyses [218,226,236,244]. These are the two best-understood cases of intra-protein proton transfer by far.…”

Section: Does the [Ser/thr] K+1 -Asp Wb Pair Accept A Proton From Wcat?mentioning

confidence: 99%

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Common mechanism of activated catalysis in P-loop fold nucleoside triphosphatases -in varietate concordia

Kozlova

Shalaeva

Dibrova

2022

Preprint

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Although P-loop fold nucleoside triphosphatases (also known as Walker NTPases) are ubiquitous, their catalytic mechanism remains obscure. Based on a comparative structural analysis of 3136 Mg-NTP-containing catalytic sites, we propose a common scheme of activated catalysis for P-loop NTPases where a hydrogen bond (H-bond) between the strictly conserved, Mg-coordinating Ser/Thr of the Walker A motif ([Ser/Thr]WA) and the conserved aspartate of the Walker B motif (AspWB) plays the key role. We found that this H-bond is very short in the structures with bound transition state (TS) analogs. We suggest that the proton affinities of these two residues reverse in the TS so that the proton relocates from [Ser/Thr]WA to AspWB. The anionic [Ser/Thr]WA withdraws then a proton from the (catalytic) water molecule, and the nascent hydroxyl anion attacks gamma-phosphate. When the gamma-phosphate group breaks away, the trapped proton relays from AspWB, via [Ser/Thr]WA, to beta-phosphate and compensates for its developing negative charge.

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Section: Is Asp Wb An Universal Trap For a Proton From Wcat?mentioning

confidence: 99%

Section: Is Asp Wb An Universal Trap For a Proton From Wcat?mentioning

confidence: 99%

Section: Does the [Ser/thr] K+1 -Asp Wb Pair Accept A Proton From Wcat?mentioning

confidence: 99%

See 1 more Smart Citation

Common mechanism of activated catalysis in P-loop fold nucleoside triphosphatases -in varietate concordia

Kozlova

Shalaeva

Dibrova

2022

Preprint

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“…The protein-water H-bond graph computed from a highresolution structure (1.05 Å) of bacteriorhodopsin [39] contains 79 H-bonding sidechains and water molecules, and 73 H-bonds between these groups (Figure 1D); when we computed the H-bond graph of the same structure without water molecules, only 19 H-bonds remained. We obtained similar results for a 1.6 Å resolution structure of Acetabularia rhodopsin I [40] (Figure 1E), whose H-bond graph has about 3.7-fold more Hbonds when both protein sidechains and water molecules are included (Figure 1F), than when water was excluded.…”

Section: Protonation Change During Gpcr Function and Ph-sensing Gpcrs...mentioning

confidence: 99%

Hydrogen-bond networks for proton couplings in G-Protein coupled receptors

Bondar

Alfonso‐Prieto

2022

Front. Phys.

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G-protein signaling pathways mediate communication across cell membranes. The first steps of this communication occur at the cell membrane, where upon receiving an external signal –the binding of an agonist ligand– the membrane-embedded G-Protein Coupled Receptor adopts a conformation recognized by a cytoplasmatic G protein. Whereas specialized GPCRs sense protons from the extracellular milieu, thus acting as pH sensors in specialized cells, accumulating evidence suggests that pH sensitivity might be common to distinct GPCRs. In this perspective article we discuss general principles of protonation-coupled protein conformational dynamics and how these apply to GPCRs. To dissect molecular interactions that might govern the protonation-coupled conformational dynamics of GPCRs, we use graph-based algorithms to compute graphs of hydrogen bond networks. We find that the internal H-bond networks contain sites where structural rearrangements upon protonation change could be transmitted throughout the protein. Proton binding to bulk-exposed clusters of titratable protein sidechains ensures the pH sensing mechanism is robust.

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“…It can be countered that the [Ser/Thr] K+1 –Asp WB pair does not interact directly with W cat . However, direct tracing of intra-protein displacements of protons in energy converting enzymes and chemical models (see [ 181 , 182 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 ] for reviews) showed that fast proton transfer over a distance of up to 20 Å can be mediated by water bridges, provided that the distance between the groups involved is ≤3.0 Å, in accordance with Eigen [ 182 ]. Thereby it does not matter that water molecules are equally poor proton acceptors (with pK b of 0.0) and proton donors (with pK a of 14.0) because protons pass water by the so-called von Grotthuss mechanism [ 210 , 211 , 212 ].…”

Section: Discussionmentioning

confidence: 99%

Common Mechanism of Activated Catalysis in P-loop Fold Nucleoside Triphosphatases—United in Diversity

et al. 2022

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To clarify the obscure hydrolysis mechanism of ubiquitous P-loop-fold nucleoside triphosphatases (Walker NTPases), we analysed the structures of 3136 catalytic sites with bound Mg-NTP complexes or their analogues. Our results are presented in two articles; here, in the second of them, we elucidated whether the Walker A and Walker B sequence motifs—common to all P-loop NTPases—could be directly involved in catalysis. We found that the hydrogen bonds (H-bonds) between the strictly conserved, Mg-coordinating Ser/Thr of the Walker A motif ([Ser/Thr]WA) and aspartate of the Walker B motif (AspWB) are particularly short (even as short as 2.4 ångströms) in the structures with bound transition state (TS) analogues. Given that a short H-bond implies parity in the pKa values of the H-bond partners, we suggest that, in response to the interactions of a P-loop NTPase with its cognate activating partner (which are analysed in the first article, reference, Biomolecules-1832854), a proton relocates from [Ser/Thr]WA to AspWB. The resulting anionic [Ser/Thr]WA alkoxide withdraws a proton from the catalytic water molecule, and the nascent hydroxyl attacks the gamma phosphate of NTP. When the gamma-phosphate breaks away, the trapped proton at AspWB passes by the Grotthuss relay via [Ser/Thr]WA to beta-phosphate and compensates for its developing negative charge that is thought to be responsible for the activation barrier of hydrolysis.

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True-atomic-resolution insights into the structure and functional role of linear chains and low-barrier hydrogen bonds in proteins

Cited by 31 publications

References 98 publications

Common mechanism of activated catalysis in P-loop fold nucleoside triphosphatases -in varietate concordia

Common mechanism of activated catalysis in P-loop fold nucleoside triphosphatases -in varietate concordia

Hydrogen-bond networks for proton couplings in G-Protein coupled receptors

Common Mechanism of Activated Catalysis in P-loop Fold Nucleoside Triphosphatases—United in Diversity

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