Limitations of Fixed-Point-Charge Force Fields for Metal Coordination Modes in Proteins: A Multilevel Study of Ca2+ in Integrin αVβ3
Abstract Standard biomolecular force fields often present limitations in modeling metal coordination modes. We combined classical and QM/MM molecular dynamics to investigate Ca2+-mediated binding of cRGD to integrin αVβ3. We show that different metal coordination modes imply variations in the partial charges of the metal-coordinating atoms, which, if incorporated in the force field, substantially alter the free energy landscape. These results highlight the value of QM-based multilevel approaches to accurately capture metal coordination modes in biomolecular systems.
Authors
- Andrea Levy (ORCID: https://orcid.org/0000-0003-1255-859X)
- Paulo Siani (ORCID: https://orcid.org/0000-0002-1930-4579)
- Cristiana Di Valentin (ORCID: https://orcid.org/0000-0003-4163-8062)
- Giulia Frigerio (ORCID: https://orcid.org/0000-0003-4517-6432)
- Ursula Röthlisberger (ORCID: https://orcid.org/0000-0002-1704-8591)
- Jules Grollier (ORCID: https://orcid.org/0009-0005-9928-0544)
Institutions
- École Polytechnique Fédérale de Lausanne (CH)
- University of Milano-Bicocca (IT)
Publication Details
- Journal
- Journal of Chemical Theory and Computation
- Published
- 2026-10-28
- DOI
- https://doi.org/10.1021/acs.jctc.6c01320
- Primary Topic
- Advanced Chemical Physics Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Ministero dell'Università e della Ricerca
- NextGenerationEU