The Existence of an Isolated Hydronium Ion in the Interior of Proteins

Ikeda, Takuya; Saito, Keisuke; Hasegawa, Ryô; Ishikita, Hiroshi

doi:10.1002/anie.201705512

Cited by 23 publications

(34 citation statements)

References 23 publications

(37 reference statements)

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“…These results concur with those by Ikeda, et al. that an explicit hydronium ion is unlikely to exist in PcyA, irrespective of the BV protonation state …”

Section: Methodssupporting

confidence: 93%

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QM/MM Investigation for Protonation States in a Bilin Reductase PcyA‐Biliverdin IXɑ Complex

et al. 2018

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Herein we report quantum mechanical/molecular mechanical (QM/MM) studies to investigate the most probable protonation states of active site amino acids and bound substrate based on a recently reported neutron diffraction structure of phycocyanobilin:ferredoxin oxidoreductase (PcyA) by Unno et al. This structure was considered to be bound in its initial state of biliverdin IXα (BV), which has the C-pyrrole ring in the deprotonated state. The protonation state of BV suggested by neutron and spectroscopic studies is a stable, two-electron reduced complex with a bound hydronium ion. Several ambiguities in the neutron structure were observed which prompted a further theoretical analysis of the structure. This structural investigation provides new understanding of the PcyA and BV protonation states not previously reported in the literature. Our calculations suggest that the hydronium ion (H O ) is energetically unfavorable, preferentially protonating the neighboring His88 residue and that the C-ring of BV is not protonated.

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“…These results concur with those by Ikeda, et al. that an explicit hydronium ion is unlikely to exist in PcyA, irrespective of the BV protonation state …”

Section: Methodssupporting

confidence: 93%

“…have reported QM/MM studies that explore the possible existence of hydronium ions in PcyA. They used BV with the deprotonated B‐ring and protonated A∼D‐pyrrole rings (referred to as 1B and 1E herein) and noted that a hydronium ion was likely to be unstable …”

Section: Methodsmentioning

confidence: 99%

QM/MM Investigation for Protonation States in a Bilin Reductase PcyA‐Biliverdin IXɑ Complex

et al. 2018

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“…In H-bonds, a proton is more likely to populate the moiety with the higher p K a value between the two moieties 26 . The energy difference between the H-bond donor and acceptor moieties corresponds to the p K a difference and this feature also holds true for H-bonds in protein environments 27 . QM/MM calculations showed that a short H-bond between H 2 O at W1 and D1-Asp61 (O W1 …O D1-Asp61 = 2.45 Å) was formed in the open-cubane S 2 (Fig.…”

Section: Resultsmentioning

confidence: 86%

“…2a ). The potential-energy profile suggested that the O W1 …O D1-Asp61 H-bond is a low-barrier H-bond (LBHB, where the p K a difference for the donor and acceptor moieties is nearly zero 25 , 27 ) (Fig. 2b ), and that the proton is significantly migrated toward D1-Asp61 and delocalized over the two moieties already in S 2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

O2 evolution and recovery of the water-oxidizing enzyme

et al. 2018

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In photosystem II, light-induced water oxidation occurs at the Mn4CaO5 cluster. Here we demonstrate proton releases, dioxygen formation, and substrate water incorporation in response to Mn4CaO5 oxidation in the protein environment, using a quantum mechanical/molecular mechanical approach and molecular dynamics simulations. In S2, H2O at the W1 site forms a low-barrier H-bond with D1-Asp61. In the S2-to-S3 transition, oxidation of OW1H– to OW1•–, concerted proton transfer from OW1H– to D1-Asp61, and binding of a water molecule Wn-W1 at OW1•– are observed. In S4, Wn-W1 facilitates oxo-oxyl radical coupling between OW1•– and corner μ-oxo O4. Deprotonation via D1-Asp61 leads to formation of OW1=O4. As OW1=O4 moves away from Mn, H2O at W539 is incorporated into the vacant O4 site of the O2-evolved Mn4CaO4 cluster, forming a μ-oxo bridge (Mn3–OW539–Mn4) in an exergonic process. Simultaneously, Wn-W1 is incorporated as W1, recovering the Mn4CaO5 cluster.

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“…52–56 Through quantum mechanics/molecular mechanics calculations, Ikeda et al have shown that isolated hydronium ion can stably exist in the interior of proteins when hydrogen bonded with acidic residues, such as aspartic and glutamic acids. 57…”

Section: Resultsmentioning

confidence: 99%

Hydronium Ions Accompanying Buried Acidic Residues Lead to High Apparent Dielectric Constants in the Interior of Proteins

Brooks

2018

J. Phys. Chem. B

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Internal ionizable groups are known to play important roles in protein functions. A mystery that has attracted decades of extensive experimental and theoretical studies is the apparent dielectric constants experienced by buried ionizable groups, which are much higher than values expected for protein interiors. Many interpretations have been proposed, such as water penetration, conformational relaxation, local unfolding, protein intrinsic backbone fluctuations, etc. However, these interpretations conflict with many experimental observations. The virtual mixture of multiple states (VMMS) simulation method developed in our lab provides a direct approach for studying the equilibrium of multiple chemical states and can monitor p K values along simulation trajectories. Through VMMS simulations of staphylococcal nuclease (SNase) variants with internal Asp or Glu residues, we discovered that cations were attracted to buried deprotonated acidic groups and the presence of the nearby cations were essential to reproduce experimentally measured p K values. This finding, combined with structural analysis and validation simulations, suggests that the proton released from a deprotonation process stays near the deprotonated group inside proteins, possibly in the form of a hydronium ion. The existence of a proton near a buried charge has many implications in our understanding of protein functions.

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The Existence of an Isolated Hydronium Ion in the Interior of Proteins

Cited by 23 publications

References 23 publications

QM/MM Investigation for Protonation States in a Bilin Reductase PcyA‐Biliverdin IXɑ Complex

QM/MM Investigation for Protonation States in a Bilin Reductase PcyA‐Biliverdin IXɑ Complex

O2 evolution and recovery of the water-oxidizing enzyme

Hydronium Ions Accompanying Buried Acidic Residues Lead to High Apparent Dielectric Constants in the Interior of Proteins

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