Bioinformatics Approaches to Predict Mutation Effects in the Binding Site of the Proangiogenic Molecule CD93

Vittoria Cicaloni; Malancha Karmakar; Luisa Frusciante; Francesco Pettini; Anna Visibelli; Maurizio Orlandini; Federico Galvagni; Maurizio Mongiat; Michael Silk; Federica Nardi; David Ascher; Annalisa Santucci; Ottavia Spiga

doi:10.3389/fbinf.2022.891553

Bioinformatics Approaches to Predict Mutation Effects in the Binding Site of the Proangiogenic Molecule CD93

Front Bioinform. 2022 Jun 21:2:891553. doi: 10.3389/fbinf.2022.891553. eCollection 2022.

Authors

Vittoria Cicaloni¹, Malancha Karmakar^{2

3

4

5}, Luisa Frusciante⁶, Francesco Pettini⁷, Anna Visibelli⁶, Maurizio Orlandini⁶, Federico Galvagni⁶, Maurizio Mongiat⁸, Michael Silk^{2

3

4

5}, Federica Nardi⁶, David Ascher^{2

3

4

5}, Annalisa Santucci⁶, Ottavia Spiga⁶

Affiliations

¹ Toscana Life Sciences Foundation, Siena, Italy.
² Structural Biology and Bioinformatics, Department of Biochemistry, University of Melbourne, Parkville, VIC, Australia.
³ Systems and Computational Biology, Bio21 Institute, University of Melbourne, Parkville, VIC, Australia.
⁴ Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
⁵ Baker Department of Cardiometabolic Health, Melbourne Medical School, University of Melbourne, Parkville, VIC, Australia.
⁶ Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
⁷ Department of Medical Biotechnologies, University of Siena, Siena, Italy.
⁸ Department of Research and Diagnosis, Division Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.

Abstract

The transmembrane glycoprotein CD93 has been identified as a potential new target to inhibit tumor angiogenesis. Recently, Multimerin-2 (MMRN2), a pan-endothelial extracellular matrix protein, has been identified as a ligand for CD93, but the interaction mechanism between these two proteins is yet to be studied. In this article, we aim to investigate the structural and functional effects of induced mutations on the binding domain of CD93 to MMRN2. Starting from experimental data, we assessed how specific mutations in the C-type lectin-like domain (CTLD) affect the binding interaction profile. We described a four-step workflow in order to predict the effects of variations on the inter-residue interaction network at the PPI, based on evolutionary information, complex network metrics, and energetic affinity. We showed that the application of computational approaches, combined with experimental data, allowed us to gain more in-depth molecular insights into the CD93-MMRN2 interaction, offering a platform for developing innovative therapeutics able to target these molecules and block their interaction. This comprehensive molecular insight might prove useful in drug design in cancer therapy.

Keywords: CD93; angiogenesis; bioinformatics; computation biology; multimerin.