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Protein-ligand co-design: a case for improving binding affinity between Type II NADH:quinone oxidoreductase and quinones
Open accessPreprint — published as 10.1007/s10822-025-00613-4 · Paper page
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 demon- strate its application to Ndh2-quinone pairings to enhance their binding affinity. Ndh2, type-II NADH dehydrogenase, is an enzyme found in certain bacteria that facilities 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
- Venue
- Journal of Computer-Aided Molecular Design
- Publisher
- openRxiv
- Published
- 2024-06-13
- Volume
- 39
- Issue
- 1
- Pages
- 39-39
- ISSN
- 0920-654X (ISSN-L)
- OpenAlex
- W4411771983
- Cited by
- 1
- References
- 1
- Citations by year
- 2025: 1
- FWCI
- 0.22
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by
- Locations
- Journal of Computer-Aided Molecular Design (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Army Research Office (W911NF-22-1-0239)
- 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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