Protonation Dynamics in the K-Channel of Cytochrome c Oxidase Estimated from Molecular Dynamics Simulations

Stegmaier, Vincent; Gorriz, Rene F.; Imhof, Petra

doi:10.3390/pr9020265

Cited by 4 publications

(10 citation statements)

References 48 publications

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“…The model setup is the same as used previously for our molecular dynamics simulations of the Pr→F redox state [ 22 ] and of the O→E state [ 14 ]. The redox state was modelled as in ref.…”

Section: Materials and Methodsmentioning

confidence: 99%

“…The first 40 ns of the simulation time was regarded as further equilibration, similar to our previous work [ 14 , 22 ], thus leaving the last 160 ns for analysis. All properties were evaluated for each of the three independent simulations separately and then averaged.…”

Section: Materials and Methodsmentioning

confidence: 99%

“…In case of protonation of K362, proton transfer to Y288, the end of the K-channel, becomes feasible [ 13 , 14 ]. In the presence of an excess charge, the tertiary structure around the K-channel has been observed to undergo conformational changes, including a widening of the channel [ 9 ], favouring or disfavouring a change in the hydration within the channel [ 13 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Hydration levels in the cavities of the BNC and in the proton-conducting channels in CcO have been studied by prediction of internal water sites and molecular dynamics simulations [ 17 , 18 , 19 ]. The formation of water wires or water chains, along which a proton transport can also take place in the channels [ 6 , 14 , 20 ] or from the BNC to the P-side and thus the exterior of the protein has been probed by simulations [ 21 ]. Higher hydration levels indeed suggest higher connectivity along water chains.…”

Section: Introductionmentioning

confidence: 99%

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Interplay of Hydration and Protonation Dynamics in the K-Channel of Cytochrome c Oxidase

Gorriz

Imhof

2022

Biomolecules

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Cytochrome c oxidase is a membrane protein of the respiratory chain that consumes protons and molecular oxygen to produce water and uses the resulting energy to pump protons across the membrane. Our molecular dynamics simulations with an excess proton located at different positions in one of the proton-conducting channels, the K-channel, show a clear dependence of the number of water molecules inside the channel on the proton position. A higher hydration level facilitates the formation of hydrogen-bonded chains along which proton transfer can occur. However, a sufficiently high hydration level for such proton transport is observed only when the excess proton is located above S365, i.e., the lower third of the channel. From the channel entrance up to this point, proton transport is via water molecules as proton carriers. These hydronium ions move with their surrounding water molecules, up to K362, filling and widening the channel. The conformation of K362 depends on its own protonation state and on the hydration level, suggesting its role to be proton transport from a hydronium ion at the height of K362 to the upper part of the channel via a conformational change. The protonation-dependent conformational dynamics of E101 at the bottom of the channel renders proton transfer via E101 unlikely. Instead, its role is rather that of an amplifier of H96’s proton affinity, suggesting H96 as the initial proton acceptor.

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Section: Materials and Methodsmentioning

confidence: 99%

Section: Materials and Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interplay of Hydration and Protonation Dynamics in the K-Channel of Cytochrome c Oxidase

Gorriz

Imhof

2022

Biomolecules

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“…This can be achieved indirectly due to the influence of the BABS ligand on the spatially distant critical residues. Besides the input E62 II , the K-channel includes residues K319, T316, and Y244, as well as water molecules located between [ 77 , 78 ]. K319 is considered to be an assailable point in this network since the conformation of its side chain flips between the “up” and “down” states during the catalytic cycle [ 79 ].…”

Section: Discussionmentioning

confidence: 99%

Interaction of Amphipathic Peptide from Influenza Virus M1 Protein with Mitochondrial Cytochrome Oxidase

Oleynikov

Sudakov

Radyukhin

et al. 2023

IJMS

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The Bile Acid Binding Site (BABS) of cytochrome oxidase (CcO) binds numerous amphipathic ligands. To determine which of the BABS-lining residues are critical for interaction, we used the peptide P4 and its derivatives A1-A4. P4 is composed of two flexibly bound modified α-helices from the M1 protein of the influenza virus, each containing a cholesterol-recognizing CRAC motif. The effect of the peptides on the activity of CcO was studied in solution and in membranes. The secondary structure of the peptides was examined by molecular dynamics, circular dichroism spectroscopy, and testing the ability to form membrane pores. P4 was found to suppress the oxidase but not the peroxidase activity of solubilized CcO. The Ki(app) is linearly dependent on the dodecyl-maltoside (DM) concentration, indicating that DM and P4 compete in a 1:1 ratio. The true Ki is 3 μM. The deoxycholate-induced increase in Ki(app) points to a competition between P4 and deoxycholate. A1 and A4 inhibit solubilized CcO with Ki(app)~20 μM at 1 mM DM. A2 and A3 hardly inhibit CcO either in solution or in membranes. The mitochondrial membrane-bound CcO retains sensitivity to P4 and A4 but acquires resistance to A1. We associate the inhibitory effect of P4 with its binding to BABS and dysfunction of the proton channel K. Trp residue is critical for inhibition. The resistance of the membrane-bound enzyme to inhibition may be due to the disordered secondary structure of the inhibitory peptide.

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Protonation-State Dependence of Hydration and Interactions in the Two Proton-Conducting Channels of Cytochrome c Oxidase

Gorriz

Volkenandt

Imhof

2023

IJMS

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Cytochrome c Oxidase (CcO), a membrane protein of the respiratory chain, pumps protons against an electrochemical gradient by using the energy of oxygen reduction to water. The (“chemical”) protons required for this reaction and those pumped are taken up via two distinct channels, named D-channel and K-channel, in a step-wise and highly regulated fashion. In the reductive phase of the catalytic cycle, both channels transport protons so that the pumped proton passes the D-channel before the “chemical” proton has crossed the K-channel. By performing molecular dynamics simulations of CcO in the O→E redox state (after the arrival of the first reducing electron) with various combinations of protonation states of the D- and K-channels, we analysed the effect of protonation on the two channels. In agreement with previous work, the amount of water observed in the D-channel was significantly higher when the terminal residue E286 was not (yet) protonated than when the proton arrived at this end of the D-channel and E286 was neutral. Since a sufficient number of water molecules in the channel is necessary for proton transport, this can be understood as E286 facilitating its own protonation. K-channel hydration shows an even higher dependence on the location of the excess proton in the K-channel. Also in agreement with previous work, the K-channel exhibits a very low hydration level that likely hinders proton transfer when the excess proton is located in the lower part of the K-channel, that is, on the N-side of S365. Once the proton has passed S365 (towards the reaction site, the bi-nuclear centre (BNC)), the amount of water in the K-channel provides hydrogen-bond connectivity that renders proton transfer up to Y288 at the BNC feasible. No significant direct effect of the protonation state of one channel on the hydration level, hydrogen-bond connectivity, or interactions between protein residues in the other channel could be observed, rendering proton conductivity in the two channels independent of each other. Regulation of the order of proton uptake and proton passage in the two channels such that the “chemical” proton leaves its channel last must, therefore, be achieved by other means of communication, such as the location of the reducing electron.

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Protonation Dynamics in the K-Channel of Cytochrome c Oxidase Estimated from Molecular Dynamics Simulations

Cited by 4 publications

References 48 publications

Interplay of Hydration and Protonation Dynamics in the K-Channel of Cytochrome c Oxidase

Interplay of Hydration and Protonation Dynamics in the K-Channel of Cytochrome c Oxidase

Interaction of Amphipathic Peptide from Influenza Virus M1 Protein with Mitochondrial Cytochrome Oxidase

Protonation-State Dependence of Hydration and Interactions in the Two Proton-Conducting Channels of Cytochrome c Oxidase

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