Biophysics of SARS-CoV-2 spike protein's receptor-binding domain interaction with ACE2 and neutralizing antibodies: from computation to functional insights

Fernando Luís Barroso da Silva^{1

2}, Karen Paco³, Aatto Laaksonen^{4

5

6

7}, Animesh Ray^{3

8}

Affiliations

¹ Departamento de Ciências Biomoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av Prof Zeferino Vaz, S/no, Ribeirão Preto, São Paulo BR-14040-903 Brazil.
² Department of Chemical and Biomolecular Engineering, NC State University, 911 Partners Way, Engineering Building I (EB1), Raleigh, NC 27695-7905 USA.
³ Riggs School of Applied Life Sciences, Keck Graduate Institute, 535 Watson Dr., Claremont, CA 91711 USA.
⁴ Department of Chemistry, Arrhenius Laboratory, Stockholm University, Svante Arrhenius Väg 8, 106 91 Stockholm, Sweden.
⁵ State Key Laboratory of Materials-Oriented and Chemical Engineering, Nanjing Tech University, NO.30 Puzhu Road(S), Nanjing, 210009 People's Republic of China.
⁶ Department of Engineering Sciences and Mathematics, Division of Energy Science, Luleå University of Technology, Laboratorievägen 14, 97187 Luleå, Sweden.
⁷ Centre of Advanced Research in Bionanoconjugates and Biopolymers, Petru Poni Institute of Macromolecular Chemistry, Aleea Grigore Ghica-Voda, 41A, 700487 Iasi, Romania.
⁸ Division of Biology and Biological Engineering, California Institute of Technology, 1200 E California Blvd, Pasadena, CA 91125 USA.

PMID: 40376405
PMCID: PMC12075047 (available on 2026-03-08)
DOI: 10.1007/s12551-025-01276-z

Review

Biophysics of SARS-CoV-2 spike protein's receptor-binding domain interaction with ACE2 and neutralizing antibodies: from computation to functional insights

Fernando Luís Barroso da Silva et al. Biophys Rev. 2025.

. 2025 Mar 8;17(2):309-333.

doi: 10.1007/s12551-025-01276-z. eCollection 2025 Apr.

Authors

Fernando Luís Barroso da Silva^{1

2}, Karen Paco³, Aatto Laaksonen^{4

5

6

7}, Animesh Ray^{3

8}

Affiliations

¹ Departamento de Ciências Biomoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av Prof Zeferino Vaz, S/no, Ribeirão Preto, São Paulo BR-14040-903 Brazil.
² Department of Chemical and Biomolecular Engineering, NC State University, 911 Partners Way, Engineering Building I (EB1), Raleigh, NC 27695-7905 USA.
³ Riggs School of Applied Life Sciences, Keck Graduate Institute, 535 Watson Dr., Claremont, CA 91711 USA.
⁴ Department of Chemistry, Arrhenius Laboratory, Stockholm University, Svante Arrhenius Väg 8, 106 91 Stockholm, Sweden.
⁵ State Key Laboratory of Materials-Oriented and Chemical Engineering, Nanjing Tech University, NO.30 Puzhu Road(S), Nanjing, 210009 People's Republic of China.
⁶ Department of Engineering Sciences and Mathematics, Division of Energy Science, Luleå University of Technology, Laboratorievägen 14, 97187 Luleå, Sweden.
⁷ Centre of Advanced Research in Bionanoconjugates and Biopolymers, Petru Poni Institute of Macromolecular Chemistry, Aleea Grigore Ghica-Voda, 41A, 700487 Iasi, Romania.
⁸ Division of Biology and Biological Engineering, California Institute of Technology, 1200 E California Blvd, Pasadena, CA 91125 USA.

PMID: 40376405
PMCID: PMC12075047 (available on 2026-03-08)
DOI: 10.1007/s12551-025-01276-z

Abstract

The spike protein encoded by the SARS-CoV-2 has become one of the most studied macromolecules in recent years due to its central role in COVID-19 pathogenesis. The spike protein's receptor-binding domain (RBD) directly interacts with the host-encoded receptor protein, ACE2. This review critically examines computational insights into RBD's interaction with ACE2 and with therapeutic antibodies designed to interfere with this interaction. We begin by summarizing insights from early computational studies on pre-pandemic SARS-CoV-1 RBD interactions and how these early studies shaped the understanding of SARS-CoV-2. Next, we highlight key theoretical contributions that revealed the molecular mechanisms behind the binding affinity of SARS-CoV-2 RBD against ACE2, and the structural changes that have enhanced the infectivity of emerging variants. Special attention is given to the "RBD charge rule", a predictive framework for determining variant infectivity based on the electrostatic properties of the RBD. Towards applying the computational insights to therapy, we discuss a multiscale computational protocol for optimizing monoclonal antibodies to improve binding affinity across multiple spike protein variants, including representatives from the Omicron family. Finally, we explore how these insights can inform the development of future vaccines and therapeutic interventions for combating future coronavirus diseases.

Keywords: Antibodies; Complexation; Electrostatic interactions; Molecular simulation; Transmissibility; Virus; pH effects.

© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2025. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

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Conflict of interest statement

Competing interestsThe authors declare no competing interests.

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Biophysics of SARS-CoV-2 spike protein's receptor-binding domain interaction with ACE2 and neutralizing antibodies: from computation to functional insights

Affiliations

Biophysics of SARS-CoV-2 spike protein's receptor-binding domain interaction with ACE2 and neutralizing antibodies: from computation to functional insights

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

LinkOut - more resources

Full Text Sources

Miscellaneous