Proton and Proton-Coupled Transport

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 20497

Special Issue Editor


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Guest Editor
Institute of Biophysics, Johannes Kepler University Linz, Gruberstraße 40, 4020 Linz, Austria
Interests: membrane transport; interfacial protons; water channels; protein–membrane translocation; membrane domains
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

I invite you to contribute to a themed issue for Biomolecules, focusing on current information on interfacial protons and their role in transporting other molecules. Such proton transfer reactions are crucial for a wide range of biological and chemical processes, starting from simple lateral proton migration along membranes, including proton channels, proton-coupled transporters, and leading to active cellular proton pumps and molecular machines that depend on the proton motive force. Even though the empirical study of proton transfer began with the origin of chemistry, many details of its concrete molecular mechanisms in different biomolecules are still unresolved. Understanding how confined water mediates proton dynamics remains a fundamental challenge in biophysics and biochemistry.

The SI appears in cooperation with the European Biophysics Society Association (EBSA) Meeting in July 2021 in Vienna, in particular with its Satellite Meeting on “Proton and Proton-Coupled Transport”. It welcomes submissions from participants of the conference.

As part of this issue, I will provide an editorial highlighting the issues raised in the various articles and possible avenues for moving the field forward.

Prof. Dr. Peter Pohl
Guest Editor

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Keywords

  • proton
  • transporter
  • channel
  • hydration
  • confinement
  • Grotthuss
  • solvation
  • Eigen cation
  • Zundel cation
  • hydronium

Published Papers (11 papers)

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Research

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23 pages, 19671 KiB  
Article
Collagen Structured Hydration
by Satyaranjan Biswal and Noam Agmon
Biomolecules 2023, 13(12), 1744; https://doi.org/10.3390/biom13121744 - 04 Dec 2023
Viewed by 1081
Abstract
Collagen is a triple-helical protein unique to the extracellular matrix, conferring rigidity and stability to tissues such as bone and tendon. For the [(PPG)10]3 collagen-mimetic peptide at room temperature, our molecular dynamics simulations show that these properties result in a [...] Read more.
Collagen is a triple-helical protein unique to the extracellular matrix, conferring rigidity and stability to tissues such as bone and tendon. For the [(PPG)10]3 collagen-mimetic peptide at room temperature, our molecular dynamics simulations show that these properties result in a remarkably ordered first hydration layer of water molecules hydrogen bonded to the backbone carbonyl (bb-CO) oxygen atoms. This originates from the following observations. The radius of gyration attests that the PPG triplets are organized along a straight line, so that all triplets (excepting the ends) are equivalent. The solvent-accessible surface area (SASA) for the bb-CO oxygens shows a repetitive regularity for every triplet. This leads to water occupancy of the bb-CO sites following a similar regularity. In the crystal-phase X-ray data, as well as in our 100 K simulations, we observe a 0-2-1 water occupancy in the P-P-G triplet. Surprisingly, a similar (0-1.7-1) regularity is maintained in the liquid phase, in spite of the sub-nsec water exchange rates, because the bb-CO sites rarely remain vacant. The manifested ordered first-shell water molecules are expected to produce a cylindrical electrostatic potential around the peptide, to be investigated in future work. Full article
(This article belongs to the Special Issue Proton and Proton-Coupled Transport)
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13 pages, 2242 KiB  
Article
A New Theory about Interfacial Proton Diffusion Revisited: The Commonly Accepted Laws of Electrostatics and Diffusion Prevail
by Denis G. Knyazev, Todd P. Silverstein, Stefania Brescia, Anna Maznichenko and Peter Pohl
Biomolecules 2023, 13(11), 1641; https://doi.org/10.3390/biom13111641 - 12 Nov 2023
Viewed by 867
Abstract
The high propensity of protons to stay at interfaces has attracted much attention over the decades. It enables long-range interfacial proton diffusion without relying on titratable residues or electrostatic attraction. As a result, various phenomena manifest themselves, ranging from spillover in material sciences [...] Read more.
The high propensity of protons to stay at interfaces has attracted much attention over the decades. It enables long-range interfacial proton diffusion without relying on titratable residues or electrostatic attraction. As a result, various phenomena manifest themselves, ranging from spillover in material sciences to local proton circuits between proton pumps and ATP synthases in bioenergetics. In an attempt to replace all existing theoretical and experimental insight into the origin of protons’ preference for interfaces, TELP, the “Transmembrane Electrostatically-Localized Protons” hypothesis, has been proposed. The TELP hypothesis envisions static H+ and OH layers on opposite sides of interfaces that are up to 75 µm thick. Yet, the separation at which the electrostatic interaction between two elementary charges is comparable in magnitude to the thermal energy is more than two orders of magnitude smaller and, as a result, the H+ and OH layers cannot mutually stabilize each other, rendering proton accumulation at the interface energetically unfavorable. We show that (i) the law of electroneutrality, (ii) Fick’s law of diffusion, and (iii) Coulomb’s law prevail. Using them does not hinder but helps to interpret previously published experimental results, and also helps us understand the high entropy release barrier enabling long-range proton diffusion along the membrane surface. Full article
(This article belongs to the Special Issue Proton and Proton-Coupled Transport)
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14 pages, 5715 KiB  
Article
Graph-Based Analyses of Dynamic Water-Mediated Hydrogen-Bond Networks in Phosphatidylserine: Cholesterol Membranes
by Honey Jain, Konstantina Karathanou and Ana-Nicoleta Bondar
Biomolecules 2023, 13(8), 1238; https://doi.org/10.3390/biom13081238 - 11 Aug 2023
Cited by 1 | Viewed by 1093
Abstract
Phosphatidylserine lipids are anionic molecules present in eukaryotic plasma membranes, where they have essential physiological roles. The altered distribution of phosphatidylserine in cells such as apoptotic cancer cells, which, unlike healthy cells, expose phosphatidylserine, is of direct interest for the development of biomarkers. [...] Read more.
Phosphatidylserine lipids are anionic molecules present in eukaryotic plasma membranes, where they have essential physiological roles. The altered distribution of phosphatidylserine in cells such as apoptotic cancer cells, which, unlike healthy cells, expose phosphatidylserine, is of direct interest for the development of biomarkers. We present here applications of a recently implemented Depth-First-Search graph algorithm to dissect the dynamics of transient water-mediated lipid clusters at the interface of a model bilayer composed of 1-palmytoyl-2-oleoyl-sn-glycero-2-phosphatidylserine (POPS) and cholesterol. Relative to a reference POPS bilayer without cholesterol, in the POPS:cholesterol bilayer there is a somewhat less frequent sampling of relatively complex and extended water-mediated hydrogen-bond networks of POPS headgroups. The analysis protocol used here is more generally applicable to other lipid:cholesterol bilayers. Full article
(This article belongs to the Special Issue Proton and Proton-Coupled Transport)
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13 pages, 4240 KiB  
Article
Fatty Acid-Activated Proton Transport by Bisaryl Anion Transporters Depolarises Mitochondria and Reduces the Viability of MDA-MB-231 Breast Cancer Cells
by Edward York, Daniel A. McNaughton, Meryem-Nur Duman, Philip A. Gale and Tristan Rawling
Biomolecules 2023, 13(8), 1202; https://doi.org/10.3390/biom13081202 - 31 Jul 2023
Viewed by 1164
Abstract
In respiring mitochondria, the proton gradient across the inner mitochondrial membrane is used to drive ATP production. Mitochondrial uncouplers, which are typically weak acid protonophores, can disrupt this process to induce mitochondrial dysfunction and apoptosis in cancer cells. We have shown that bisaryl [...] Read more.
In respiring mitochondria, the proton gradient across the inner mitochondrial membrane is used to drive ATP production. Mitochondrial uncouplers, which are typically weak acid protonophores, can disrupt this process to induce mitochondrial dysfunction and apoptosis in cancer cells. We have shown that bisaryl urea-based anion transporters can also mediate mitochondrial uncoupling through a novel fatty acid-activated proton transport mechanism, where the bisaryl urea promotes the transbilayer movement of deprotonated fatty acids and proton transport. In this paper, we investigated the impact of replacing the urea group with squaramide, amide and diurea anion binding motifs. Bisaryl squaramides were found to depolarise mitochondria and reduce MDA-MB-231 breast cancer cell viability to similar extents as their urea counterpart. Bisaryl amides and diureas were less active and required higher concentrations to produce these effects. For all scaffolds, the substitution of the bisaryl rings with lipophilic electron-withdrawing groups was required for activity. An investigation of the proton transport mechanism in vesicles showed that active compounds participate in fatty acid-activated proton transport, except for a squaramide analogue, which was sufficiently acidic to act as a classical protonophore and transport protons in the absence of free fatty acids. Full article
(This article belongs to the Special Issue Proton and Proton-Coupled Transport)
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13 pages, 2063 KiB  
Article
Proton Migration on Top of Charged Membranes
by Ewald Weichselbaum, Timur Galimzyanov, Oleg V. Batishchev, Sergey A. Akimov and Peter Pohl
Biomolecules 2023, 13(2), 352; https://doi.org/10.3390/biom13020352 - 11 Feb 2023
Cited by 5 | Viewed by 1478
Abstract
Proton relay between interfacial water molecules allows rapid two-dimensional diffusion. An energy barrier, ΔGr, opposes proton-surface-to-bulk release. The ΔGr-regulating mechanism thus far has remained unknown. Here, we explored the effect interfacial charges have on [...] Read more.
Proton relay between interfacial water molecules allows rapid two-dimensional diffusion. An energy barrier, ΔGr, opposes proton-surface-to-bulk release. The ΔGr-regulating mechanism thus far has remained unknown. Here, we explored the effect interfacial charges have on ΔGr’s enthalpic and entropic constituents, ΔGH and ΔGS, respectively. A light flash illuminating a micrometer-sized membrane patch of a free-standing planar lipid bilayer released protons from an adsorbed hydrophobic caged compound. A lipid-anchored pH-sensitive dye reported protons’ arrival at a distant membrane patch. Introducing net-negative charges to the bilayer doubled ΔGH, while positive net charges decreased ΔGH. The accompanying variations in ΔGS compensated for the ΔGH modifications so that ΔGr was nearly constant. The increase in the entropic component of the barrier is most likely due to the lower number and strength of hydrogen bonds known to be formed by positively charged residues as compared to negatively charged moieties. The resulting high ΔGr ensured interfacial proton diffusion for all measured membranes. The observation indicates that the variation in membrane surface charge alone is a poor regulator of proton traffic along the membrane surface. Full article
(This article belongs to the Special Issue Proton and Proton-Coupled Transport)
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13 pages, 1422 KiB  
Article
Modulation of Anionic Lipid Bilayers by Specific Interplay of Protons and Calcium Ions
by Abhinav, Piotr Jurkiewicz, Martin Hof, Christoph Allolio and Jan Sýkora
Biomolecules 2022, 12(12), 1894; https://doi.org/10.3390/biom12121894 - 17 Dec 2022
Cited by 1 | Viewed by 1495
Abstract
Biomembranes, important building blocks of living organisms, are often exposed to large local fluctuations of pH and ionic strength. To capture changes in the membrane organization under such harsh conditions, we investigated the mobility and hydration of zwitterionic and anionic lipid bilayers upon [...] Read more.
Biomembranes, important building blocks of living organisms, are often exposed to large local fluctuations of pH and ionic strength. To capture changes in the membrane organization under such harsh conditions, we investigated the mobility and hydration of zwitterionic and anionic lipid bilayers upon elevated H3O+ and Ca2+ content by the time-dependent fluorescence shift (TDFS) technique. While the zwitterionic bilayers remain inert to lower pH and increased calcium concentrations, anionic membranes are responsive. Specifically, both bilayers enriched in phosphatidylserine (PS) and phosphatidylglycerol (PG) become dehydrated and rigidified at pH 4.0 compared to at pH 7.0. However, their reaction to the gradual Ca2+ increase in the acidic environment differs. While the PG bilayers exhibit strong rehydration and mild loosening of the carbonyl region, restoring membrane properties to those observed at pH 7.0, the PS bilayers remain dehydrated with minor bilayer stiffening. Molecular dynamics (MD) simulations support the strong binding of H3O+ to both PS and PG. Compared to PS, PG exhibits a weaker binding of Ca2+ also at a low pH. Full article
(This article belongs to the Special Issue Proton and Proton-Coupled Transport)
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21 pages, 3076 KiB  
Article
Interplay of Hydration and Protonation Dynamics in the K-Channel of Cytochrome c Oxidase
by Rene F. Gorriz and Petra Imhof
Biomolecules 2022, 12(11), 1615; https://doi.org/10.3390/biom12111615 - 01 Nov 2022
Cited by 2 | Viewed by 1365
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Proton and Proton-Coupled Transport)
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14 pages, 3791 KiB  
Article
Mitochondrial Uncoupling Proteins (UCP1-UCP3) and Adenine Nucleotide Translocase (ANT1) Enhance the Protonophoric Action of 2,4-Dinitrophenol in Mitochondria and Planar Bilayer Membranes
by Kristina Žuna, Olga Jovanović, Ljudmila S. Khailova, Sanja Škulj, Zlatko Brkljača, Jürgen Kreiter, Elena A. Kotova, Mario Vazdar, Yuri N. Antonenko and Elena E. Pohl
Biomolecules 2021, 11(8), 1178; https://doi.org/10.3390/biom11081178 - 09 Aug 2021
Cited by 14 | Viewed by 4377
Abstract
2,4-Dinitrophenol (DNP) is a classic uncoupler of oxidative phosphorylation in mitochondria which is still used in “diet pills”, despite its high toxicity and lack of antidotes. DNP increases the proton current through pure lipid membranes, similar to other chemical uncouplers. However, the molecular [...] Read more.
2,4-Dinitrophenol (DNP) is a classic uncoupler of oxidative phosphorylation in mitochondria which is still used in “diet pills”, despite its high toxicity and lack of antidotes. DNP increases the proton current through pure lipid membranes, similar to other chemical uncouplers. However, the molecular mechanism of its action in the mitochondria is far from being understood. The sensitivity of DNP’s uncoupling action in mitochondria to carboxyatractyloside, a specific inhibitor of adenine nucleotide translocase (ANT), suggests the involvement of ANT and probably other mitochondrial proton-transporting proteins in the DNP’s protonophoric activity. To test this hypothesis, we investigated the contribution of recombinant ANT1 and the uncoupling proteins UCP1-UCP3 to DNP-mediated proton leakage using the well-defined model of planar bilayer lipid membranes. All four proteins significantly enhanced the protonophoric effect of DNP. Notably, only long-chain free fatty acids were previously shown to be co-factors of UCPs and ANT1. Using site-directed mutagenesis and molecular dynamics simulations, we showed that arginine 79 of ANT1 is crucial for the DNP-mediated increase of membrane conductance, implying that this amino acid participates in DNP binding to ANT1. Full article
(This article belongs to the Special Issue Proton and Proton-Coupled Transport)
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Review

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34 pages, 4084 KiB  
Review
Voltage-Gated Proton Channels in the Tree of Life
by Gustavo Chaves, Christophe Jardin, Christian Derst and Boris Musset
Biomolecules 2023, 13(7), 1035; https://doi.org/10.3390/biom13071035 - 24 Jun 2023
Cited by 2 | Viewed by 2119
Abstract
With a single gene encoding HV1 channel, proton channel diversity is particularly low in mammals compared to other members of the superfamily of voltage-gated ion channels. Nonetheless, mammalian HV1 channels are expressed in many different tissues and cell types [...] Read more.
With a single gene encoding HV1 channel, proton channel diversity is particularly low in mammals compared to other members of the superfamily of voltage-gated ion channels. Nonetheless, mammalian HV1 channels are expressed in many different tissues and cell types where they exert various functions. In the first part of this review, we regard novel aspects of the functional expression of HV1 channels in mammals by differentially comparing their involvement in (1) close conjunction with the NADPH oxidase complex responsible for the respiratory burst of phagocytes, and (2) in respiratory burst independent functions such as pH homeostasis or acid extrusion. In the second part, we dissect expression of HV channels within the eukaryotic tree of life, revealing the immense diversity of the channel in other phylae, such as mollusks or dinoflagellates, where several genes encoding HV channels can be found within a single species. In the last part, a comprehensive overview of the biophysical properties of a set of twenty different HV channels characterized electrophysiologically, from Mammalia to unicellular protists, is given. Full article
(This article belongs to the Special Issue Proton and Proton-Coupled Transport)
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12 pages, 1357 KiB  
Review
Local Attraction of Substrates and Co-Substrates Enhances Weak Acid and Base Transmembrane Transport
by Nathan Hugo Epalle and Eric Beitz
Biomolecules 2022, 12(12), 1794; https://doi.org/10.3390/biom12121794 - 30 Nov 2022
Viewed by 1267
Abstract
The transmembrane transport of weak acid and base metabolites depends on the local pH conditions that affect the protonation status of the substrates and the availability of co-substrates, typically protons. Different protein designs ensure the attraction of substrates and co-substrates to the transporter [...] Read more.
The transmembrane transport of weak acid and base metabolites depends on the local pH conditions that affect the protonation status of the substrates and the availability of co-substrates, typically protons. Different protein designs ensure the attraction of substrates and co-substrates to the transporter entry sites. These include electrostatic surface charges on the transport proteins and complexation with seemingly transport-unrelated proteins that provide substrate and/or proton antenna, or enzymatically generate substrates in place. Such protein assemblies affect transport rates and directionality. The lipid membrane surface also collects and transfers protons. The complexity in the various systems enables adjustability and regulation in a given physiological or pathophysiological situation. This review describes experimentally shown principles in the attraction and facilitation of weak acid and base transport substrates, including monocarboxylates, ammonium, bicarbonate, and arsenite, plus protons as a co-substrate. Full article
(This article belongs to the Special Issue Proton and Proton-Coupled Transport)
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25 pages, 9721 KiB  
Review
Biomimetic Artificial Proton Channels
by Iuliana-Marilena Andrei and Mihail Barboiu
Biomolecules 2022, 12(10), 1473; https://doi.org/10.3390/biom12101473 - 13 Oct 2022
Cited by 4 | Viewed by 2307
Abstract
One of the most common biochemical processes is the proton transfer through the cell membranes, having significant physiological functions in living organisms. The proton translocation mechanism has been extensively studied; however, mechanistic details of this transport are still needed. During the last decades, [...] Read more.
One of the most common biochemical processes is the proton transfer through the cell membranes, having significant physiological functions in living organisms. The proton translocation mechanism has been extensively studied; however, mechanistic details of this transport are still needed. During the last decades, the field of artificial proton channels has been in continuous growth, and understanding the phenomena of how confined water and channel components mediate proton dynamics is very important. Thus, proton transfer continues to be an active area of experimental and theoretical investigations, and acquiring insights into the proton transfer mechanism is important as this enlightenment will provide direct applications in several fields. In this review, we present an overview of the development of various artificial proton channels, focusing mostly on their design, self-assembly behavior, proton transport activity performed on bilayer membranes, and comparison with protein proton channels. In the end, we discuss their potential applications as well as future development and perspectives. Full article
(This article belongs to the Special Issue Proton and Proton-Coupled Transport)
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