Journal Article

FZJ-2026-02012

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Protonation-dependent substrate release in a bacterial homolog of vesicular glutamate

Plate, C. ; Dmitrieva, N.FZJ* ; Gholami, S. ; Alfonso-Prieto, M.FZJ* ; Deshmukh, S. A. ; Mandelli, D. (Corresponding author)FZJ* ; Carloni, P. (Corresponding author)FZJ* ; Fahlke, C.FZJ*

2026
Cell Press Cambridge, Mass.

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Please use a persistent id in citations: doi:10.1016/j.bpj.2026.02.027

Abstract: The SLC17 family contains diverse organic anion transporters with various stoichiometries and ion couplingmechanisms. A bacterial protein of this family, the D-galactonate transporter DgoT, co-transports two protons per substratemolecule. Although the overall transport cycle of DgoT has been proposed, the role of substrate protonation during its releaseremains unclear. Galactonate is expected to bind in a deprotonated form due to its low pKa; however, it can be released from thetransporter in either a protonated or deprotonated state. In this study, we used well-tempered funnel metadynamics simulationsto investigate the microscopic mechanisms underlying protonated and deprotonated galactonate dissociation from the inward-facing, gate-open conformation of DgoT. Our free energy profiles reveal that, although substrate protonation lowers the energybarrier for release and may enhance dissociation kinetics, deprotonated galactonate can also dissociate, albeit less frequently.These findings indicate that galactonate protonation facilitates, but is not strictly required for, substrate release by the bacterialorganic anion transporter DgoT.

Note: C.P. gratefully acknowledges funding from the ‘‘Algorithms & Software forSUpercomputers with emerging aRchitEctures (ASSURE)’’ NSF-fundedInternational Research Experiences for Students (IRES). D.M. and P.C.acknowledge support by the European Union’s HORIZON MSCA DoctoralNetworks program, under Grant Agreement No. 101072344, project AQTI-VATE (Advanced computing, QuanTum algorIthms and datadriVen Ap-proaches for Science, Technology, and Engineering). This work was alsosupported by the Deutsche Forschungsgemeinschaft (German ResearchFoundation) to C.F. (FA 301/15–2), P.C. (CA 973/27-2), and M.A.-P. (AL2511/1-2) as part of Research Unit FOR 2518, DynIon. The authors grate-fully acknowledge the Advanced Research Computing (ARC) facility atVirginia Tech, and computing time on the supercomputer JURECA (16)at Forschungszentrum Ju¨lich under grant no. dgot-gal.

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Contributing Institute(s):

1. Molekular- und Zellphysiologie (IBI-1)
2. Computational Biomedicine (INM-9)

Research Program(s):

1. 5241 - Molecular Information Processing in Cellular Systems (POF4-524) (POF4-524)
2. DFG project G:(GEPRIS)426950122 - FOR 5046: Integrative Analyse epithelialer SLC26 Anionentransporter – von der molekularen Struktur zur Pathophysiologie (426950122) (426950122)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF < 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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