Unveiling the affinity-stability relationship in anti-measles virus antibodies: a computational approach for hotspots prediction

Rimpa Paul; Keisuke Kasahara; Jiei Sasaki; Jorge Fernández Pérez; Ryo Matsunaga; Takao Hashiguchi; Daisuke Kuroda; Kouhei Tsumoto

doi:10.3389/fmolb.2023.1302737

Unveiling the affinity-stability relationship in anti-measles virus antibodies: a computational approach for hotspots prediction

Front Mol Biosci. 2024 Mar 1:10:1302737. doi: 10.3389/fmolb.2023.1302737. eCollection 2023.

Authors

Rimpa Paul^{1

2}, Keisuke Kasahara¹, Jiei Sasaki³, Jorge Fernández Pérez¹, Ryo Matsunaga^{1

4}, Takao Hashiguchi³, Daisuke Kuroda^{1

2

4}, Kouhei Tsumoto^{1

4

5}

Affiliations

¹ Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan.
² Research Center of Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, Japan.
³ Institute for Life and Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
⁴ Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo, Japan.
⁵ The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Abstract

Recent years have seen an uptick in the use of computational applications in antibody engineering. These tools have enhanced our ability to predict interactions with antigens and immunogenicity, facilitate humanization, and serve other critical functions. However, several studies highlight the concern of potential trade-offs between antibody affinity and stability in antibody engineering. In this study, we analyzed anti-measles virus antibodies as a case study, to examine the relationship between binding affinity and stability, upon identifying the binding hotspots. We leverage in silico tools like Rosetta and FoldX, along with molecular dynamics (MD) simulations, offering a cost-effective alternative to traditional in vitro mutagenesis. We introduced a pattern in identifying key residues in pairs, shedding light on hotspots identification. Experimental physicochemical analysis validated the predicted key residues by confirming significant decrease in binding affinity for the high-affinity antibodies to measles virus hemagglutinin. Through the nature of the identified pairs, which represented the relative hydropathy of amino acid side chain, a connection was proposed between affinity and stability. The findings of the study enhance our understanding of the interactions between antibody and measles virus hemagglutinin. Moreover, the implications of the observed correlation between binding affinity and stability extend beyond the field of anti-measles virus antibodies, thereby opening doors for advancements in antibody research.

Keywords: antibody engineering; computer-aided design; hotspots; measles virus hemagglutinin; molecular dynamics; relative hydropathy.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was funded in part by the Japan Society for the Promotion of Science (JP 20K20596 to TH, JP19H04202 and JP21K18310 to DK, JP19H05766 and JP20H02531 to KT) and the Japan Agency for Medical Research and Development (JP22wm0325047 and JP23wm0325069 to TH and DK, JP22ama121033 to KT). We also thanks to Okawa Foundation for Information and Telecommunications (grant number 20-10 to DK), the Sumitomo foundation (to TH) and the Naito foundation (to TH).