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Protein-ligand co-design: a case for improving binding affinity between type II NADH:quinone oxidoreductase and quinones

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Porokhin, Vladimir, Brown, Anne M., Hassoun, Soha·2025·Journal of Computer-Aided Molecular Design
DOI 10.1007/s10822-025-00613-4

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Abstract

Biological engineering aims to enhance biological systems by designing proteins with improved catalytic properties or ligands with enhanced function. Typically, applications permit designing proteins, e.g., an enzyme in a biodegradation reaction, or ligands e.g., a drug for a target receptor, but not both. Yet, some applications can benefit from a more flexible approach where both the protein and ligand can be designed or modified together to enhance a desired property. To meet the need for this co-design capability, we introduce a novel co-design paradigm and demonstrate its application to Ndh2-quinone pairings to enhance their binding affinity. Ndh2, type-II NADH dehydrogenase, is an enzyme found in certain bacteria that facilitates extracellular electron transfer (EET) when interacting with exogenous quinone mediators. This interaction leads to the generation of a detectable electric current that can be used for biosensing applications. Our results demonstrate the benefits of the co-design paradigm in realizing Ndh2-quinone pairings with enhanced binding affinities, therefore highlighting the importance of considering protein-ligand engineering from a holistic co-design perspective.

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Metadata

Authors
Porokhin, V., Brown, A. M., & Hassoun, S.
Affiliations
  • Tufts University (US)
  • Virginia Tech (US)
Corresponding author
Hassoun, Soha
ORCID
Venue
Journal of Computer-Aided Molecular Design
Publisher
Springer Science and Business Media LLC
Published
2025-06-29
Volume
39
Issue
1
Pages
39-39
ISSN
  • 0920-654X (ISSN-L)
  • 1573-4951
DOI
10.1007/s10822-025-00613-4
OpenAlex
W4411771983
Cited by
1
References
5
Citations by year
2025: 1
FWCI
0.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Computer-Aided Molecular Design (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Army Research Office (W911NF2210239)
Topics
  • Physical Sciences › Chemistry › Analytical Chemistry › Electrochemical sensors and biosensors
  • Physical Sciences › Environmental Science › Environmental Engineering › Microbial Fuel Cells and Bioremediation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme Catalysis and Immobilization
Keywords
NDH-2, extracellular electron transfer, biosensing, enzyme engineering, ligand engineering
MeSH terms
Binding Sites, Electron Transport, Ligands, Models, Molecular, NADH Dehydrogenase, Protein Binding, Quinone Reductases, Quinones, Protein Engineering

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