Electrostatic basis for the unidirectionality of the primary proton transfer in cytochrome
            <i>c</i>
            oxidase

Pisliakov, Andrei V.; Sharma, Pramod Kumar; Chu, Zhen T.; Harańczyk, Maciej; Warshel, Arieh

doi:10.1073/pnas.0800580105

Cited by 88 publications

(130 citation statements)

References 36 publications

(69 reference statements)

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“…Previous calculations have reprotonated E286 before (30) or after (32) electron transfer to the BNC. Simulations by Warshel, who considered many possible electron and proton transfer sequences, found the lowest energy barrier when the electron transfer to the BNC occurs before reprotonation of E286 (29,32). The protonation of the PRD of heme a 3 may open a cavity near E286 (26); this is calculated to significantly lower the proton affinity of E286, stabilizing its deprotonated state for proton transfer to the BNC.…”

Section: Significancementioning

confidence: 99%

“…The propionic acids on the A (PRA) or D (PRD) rings of heme a 3 (26) or His A334, which is a ligand to Cu B , have all been proposed to be the PLS (15,24,27,28). The energetics and pathway of proton pumping has been simulated assuming the PRD of heme a 3 is the PLS (26,(29)(30)(31)(32). Because there are many ionizable groups on the P-side, the PLS could also be made up of a cluster of residues rather than a single site (SI Appendix, Fig.…”

Section: Significancementioning

confidence: 99%

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Characterizing the proton loading site in cytochromecoxidase

Gunner

2014

Proc. Natl. Acad. Sci. U.S.A.

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Cytochrome c oxidase (CcO) uses the energy released by reduction of O 2 to H 2 O to drive eight charges from the high pH to low pH side of the membrane, increasing the electrochemical gradient. Four electrons and protons are used for chemistry, while four more protons are pumped. Proton pumping requires that residues on a pathway change proton affinity through the reaction cycle to load and then release protons. The protonation states of all residues in CcO are determined in MultiConformational Continuum Electrostatics simulations with the protonation and redox states of heme a, a 3 , Cu B , Y288, and E286 used to define the catalytic cycle. One proton is found to be loaded and released from residues identified as the proton loading site (PLS) on the P-side of the protein in each of the four CcO redox states. Thus, the same proton pumping mechanism can be used each time CcO is reduced. Calculations with structures of Rhodobacter sphaeroides, Paracoccus denitrificans, and bovine CcO derived by crystallography and molecular dynamics show the PLS functions similarly in different CcO species. The PLS is a cluster rather than a single residue, as different structures show 1-4 residues load and release protons. However, the proton affinity of the heme a 3 propionic acids primarily determines the number of protons loaded into the PLS; if their proton affinity is too low, less than one proton is loaded.MCCE | bioenergetics | pK a | proton transfer

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Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Characterizing the proton loading site in cytochromecoxidase

Gunner

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Free energy calculations and MD simulations successfully predict the hydration state of pockets of different chemical natures (polar vs nonpolar) 22,50,51,53 , help to understand the relation between internal hydration and function as in the case of charge separation processes [54][55][56][57] , ligand binding [58][59][60] , allostery 61,62 and can be used to estimate the contribution to stability 50,63 .…”

Section: Introductionmentioning

confidence: 99%

Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains

et al. 2014

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In this work we address the question whether the enhanced stability of thermophilic proteins has a direct connection with internal hydration. Our model systems are two homologues G-domains of different stability: the mesophilic G domain of the Elongation-Factor thermal unstable protein from E. coli and the hyperthermophilic G domain of the EF-α protein from S. solfataricus. Using molecular dynamics simulation at the microsecond time-scale we show that both proteins host water molecules in internal cavities and that these molecules exchange with the external solution in the nanosecond time scale. The hydration free energy of these sites evaluated via extensive calculations is found to be favourable for both systems, with the hyperthermophilic protein offering a slightly more favourable environment to host water molecules. We estimate that under ambient conditions, the free energy gain due to internal hydration is about 1.3 kcal/mol in favor of the hyperthermophilic variant. However, we also find that at the high working temperature of the hyperthermophile, the cavities are rather dehydrated, meaning that at extreme conditions other molecular factors secure the stability of the protein. Interestingly, we detect a clear correlation between the hydration of internal cavities and the protein conformational landscape. The emerging picture is that internal hydration is an effective observable to probe the conformational landscape of proteins. In the specific context of our investigation, the analysis confirms that the hyperthermophilic G-domain is characterized by multiple states and it has a more flexible structure than its mesophilic homologue.

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“…From a broader perspective, these observations demonstrate that ionization-resistant hydroxyl groups, such as serine and threonine (or other residues with a locally high pK a 48,49 ) can be H-bonded within a proton wire and still actively participate via deep proton tunneling. Wellaligned proton wires that are composed solely of water molecules are known to be extremely efficient charge carriers that can transport an excess proton on a sub-ps timescale 25 ; however, these water structures can be unstable, especially when long distances need to be traversed 50 .…”

Section: Discussionmentioning

confidence: 99%

“…It has been proposed that the hydroxyl residue must be protonated to -OH 2 + in order to make transport to the adjoining neutral water possible 17 , but such a protonation step has very low probability. Generally, when a classical approach is used, large barriers associated with high pK a residues in the protein interior 48,49 will lead to such slow rates that these residues must be excluded. In contrast, the experimental results presented here demonstrate that such residues can play an active role in proton wires via deep tunneling and suggest a natural way for the protein to control the direction of proton flow.…”

Section: Discussionmentioning

confidence: 99%

Wide-dynamic-range kinetic investigations of deep proton tunnelling in proteins

et al. 2016

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Abstract:Directional proton transport along "wires" that feed biochemical reactions in proteins is poorly understood. Amino acid residues with high pK a are seldom considered as active transport elements in such wires because of their large classical barrier for proton dissociation. Here we use the light-triggered proton wire of the green fluorescent protein (GFP) to study its ground electronic state proton transport kinetics, revealing a large temperature-dependent kinetic isotope effect. We show that "deep" proton tunneling between hydrogen-bonded oxygen atoms having a typical donor-acceptor distance of 2.7-2.8 Ǻ fully accounts for the rates at all temperatures, including the unexpectedly large value (2.5 10 9 s -1 ) found at room temperature. The rate limiting step in GFP is assigned to tunneling of the ionization-resistant serine hydroxyl proton. This suggests how high pK a residues within a proton wire can act as a "tunnel-diode" to kinetically trap protons and control the direction of proton flow.

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Electrostatic basis for the unidirectionality of the primary proton transfer in cytochrome c oxidase

Cited by 88 publications

References 36 publications

Characterizing the proton loading site in cytochromecoxidase

Characterizing the proton loading site in cytochromecoxidase

Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains

Wide-dynamic-range kinetic investigations of deep proton tunnelling in proteins

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