Secure, competitive, and sustainable energy production is a major challenge facing human societies. Biomimetic solutions such as the development of new biofuel cells are hampered by our thus far incomplete understanding of proton transfer reactions. The same holds for health threats to humanity: Curing diseases like cancer, obesity, chronic gastritis, gastric and duodenal ulcers, requires to pharmacologically interfere - in their molecular details - with yet unresolved proton transfer reactions.

Here we aim at clarifying the molecular reaction mechanism in the confines of interfacial water layers and proteinaceous cavities with emphasis on arrangement and mobility of proton relay moieties. Achieving this requires an interdisciplinary, multi-level approach comprising cutting edge technologies like second harmonic imaging, single molecule and time resolved fluorescence microscopy and spectroscopy, advanced calculations of proton transfer, bioengineering of membrane channel and transporter containing systems, synthetic design of biomimetic proton channels, solving protein structures and rational drug design.

PROTON will train 15 PhD students, who will acquire a solid state-of-the-art multidisciplinary scientific training in all kinds of proton migration/reaction systems, covering from basic science to industrial applications, thus preparing them to generate new scientific knowledge of the highest impact. In addition, practical training on transferable skills will increase their employability and qualify them for responsible positions in private and public sectors. Cross-disciplinary strategies and close collaboration with industry will enable them to resolve the molecular details of proton driven processes in all kinds of settings - enabling the improvement of biomimetic applications – up to fuel cells - and to identify lead substances which may serve to pharmacologically interfere with proton transport through membrane channels and transporters.

Proton transfer is crucial in numerous biological and chemical processes, e.g. in cellular proton pumps or in hydrogen fuel cells. Even though their empirical study began with the origin of chemistry, many details of the proton transfer mechanism are still unresolved and understanding the way in which confined water mediates proton dynamics remains a fundamental challenge in chemistry and biochemistry. Transmembrane proton gradients are essential to life on earth as they are intricately linked to both photosynthesis and synthesis of adenosine triphosphate (ATP, the energy currency of life). Yet, once protons have crossed the membrane, they do not freely exchange with protons on the receiving site. An energy barrier with the height of ~30 kT opposes their release into the bulk. The mainly entropic nature of the barrier ensures high lateral proton mobility. However, besides being attributed to structured water,^,the molecular origin of that barrier remained thus far elusive. Yet, newly developed label-free and charge-sensitive dynamic imaging techniques of lipid membrane hydration, hydration of active protein sites as well as their dipolar relaxation dynamics now offer the possibility to explore the interplay between structural features of the hydration shell and proton migration on the millisecond time scale. Likewise, technically demanding ab-initio molecular dynamics (MD) simulations of protons adjacent to lipid bilayers also promise insight into the molecular proton migration mechanism. By levering on these new methods for (i) visualising proton surface transport as well as (ii) assessing its energetics and combining them with approaches for deciphering the structure of G-protein-coupled receptors (GPCRs) and other proton-dependent membrane protein, the PROTON project will perform ground-breaking work in this field.

Abhinav, Jurkiewicz P, Hof M, Allolio C, Sýkora J. Modulation of Anionic Lipid Bilayers by Specific Interplay of Protons and Calcium Ions, öffnet eine externe URL in einem neuen Fenster. Biomolecules. 2022 Dec 17;12(12):1894. doi: 10.3390/biom12121894. PMID: 36551322; PMCID: PMC9775051.

Geistlinger K, Schmidt JDR, Beitz E. Lactic Acid Permeability of Aquaporin-9 Enables Cytoplasmic Lactate Accumulation via an Ion Trap., öffnet eine externe URL in einem neuen Fenster Life. 2022;12(1):120. doi.org/10.3390/life12010120

Andrei I-M, Barboiu M. Biomimetic Artificial Proton Channels., öffnet eine externe URL in einem neuen Fenster Biomolecules.2022; 12(10):1473. doi.org/10.3390/biom12101473 

Žuna K, Jovanović O, Khailova LS, Škulj S, Brkljača Z, Kreiter J, Kotova EA, Vazdar M, Antonenko YN, Pohl EE. Mitochondrial Uncoupling Proteins (UCP1-UCP3) and Adenine Nucleotide Translocase (ANT1) Enhance the Protonophoric Action of 2,4-Dinitrophenol in Mitochondria and Planar Bilayer Membranes. Biomolecules., öffnet eine Datei 2021 Aug 9;11(8):1178. doi: 10.3390/biom11081178. PMID: 34439844; PMCID: PMC8392417.

Nerlich C, Epalle NH, Seick P, Beitz E. Discovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials, öffnet eine Datei. Pharmaceuticals (Basel). 2021 Nov 20;14(11):1191. doi: 10.3390/ph14111191. PMID: 34832972; PMCID: PMC8624176.

Jakobowska I, Becker F, Minguzzi S, Hansen K, Henke B, Epalle NH, Beitz E, Hannus S. Fluorescence Cross-Correlation Spectroscopy Yields True Affinity and Binding Kinetics of Plasmodium Lactate Transport Inhibitors, öffnet eine Datei. Pharmaceuticals (Basel). 2021 Aug 2;14(8):757. doi: 10.3390/ph14080757. PMID: 34451854; PMCID: PMC8399565.

Lee S, Roesel D, Roke S. Imaging Cu2+ binding to charged phospholipid membranes by high-throughput second harmonic wide-field microscopy, öffnet eine externe URL in einem neuen Fenster. J Chem Phys. 2021 Nov 14;155(18):184704. doi: 10.1063/5.0063362. PMID: 34773948.

Licsandru E, Andrei IM, van der Lee A, Barboiu M. Self-Assembled H-Bonding Superstructures for Alkali Cation and Proton Transport, öffnet eine Datei. Front Chem. 2021 May 6;9:678962. doi: 10.3389/fchem.2021.678962. PMID: 34026736; PMCID: PMC8134729.

Köpnick AL, Jansen A, Geistlinger K, Epalle NH, Beitz E.Basigin drives intra cellular accumulation of l-lactate by harvesting protons and substrate anions, öffnet eine Datei. PLoS One. 2021 Mar 26;16(3):e0249110. doi: 10.1371/journal.pone.0249110. PMID: 33770122; PMCID: PMC7996999

Beneficiaries

Partner Organisations

Contact

KICK-OFF MEETING: 13.09.2019 - 15.09.2019 in Strobl

2nd TRAINING EVENT/ MID-TERM EVALUATION:, öffnet eine Datei 12.11.2020 - 18.11.2020 via ZOOM

3rd TRAINING EVENT:, öffnet eine Datei 23.03.2021-26.03.2021 via ZOOM

1st TRAINING EVENT/ EBSA SATELLITE MEETING, öffnet eine Datei in einem neuen Fenster: 22. - 24. July 2021 in Vienna

4th TRAINING EVENT: , öffnet eine Datei06.04.2022 -08.04.2022 in Biberach, Germany 

5th Training Event:, öffnet eine Datei 09.11.2022-12.11.2022 in Martinsried, Germany 

Final conference 18.07-21.07.2023 in Traunkirchen, Austria 

Ph.D. student in biophysics/Physical Chemistry | EURAXESS (europa.eu), öffnet eine externe URL in einem neuen Fenster

Ph.D. student in Supramolecular Chemistry | EURAXESS (europa.eu), öffnet eine externe URL in einem neuen Fenster