Prediction of the binding interface between monoclonal antibody m102.4 and Nipah attachment glycoprotein using structure-guided alanine scanning and computational docking

Abstract

Nipah Virus (NiV) has been designated as a priority disease with an urgent need for therapeutic development by World Health Organization. The monoclonal antibody m102.4 binds to the immunodominant NiV receptor-binding glycoprotein (GP), and potently neutralizes NiV, indicating its potential as a therapeutic agent. Although the co-crystal structure of m102.3, an m102.4 derivative, in complex with the GP of the related Hendra Virus (HeV) has been solved, the structural interaction between m102.4 and NiV is uncharacterized. Herein, we used structure-guided alanine-scanning mutagenesis to map the functional epitope and paratope residues that govern the antigen–antibody interaction. Our results revealed that the binding of m102.4 is mediated predominantly by two residues in the HCDR3 region, which is unusually small for an antibody-antigen interaction. We performed computational docking to generate a structural model of m102.4-NiV interaction. Our model indicates that m102.4 targets the common hydrophobic central cavity and a hydrophilic rim on the GP, as observed for the m102.3-HeV co-crystal, albeit with Fv orientation differences. In summary, our study provides insight into the m102.4-NiV interaction, demonstrating that structure-guided alanine-scanning and computational modeling can serve as the starting point for additional antibody reengineering (e.g. affinity maturation) to generate potential therapeutic candidates.

Prediction of the structural interface between fibroblast growth factor23 and Burosumab using alanine scanning and molecular docking

“…We used BIOVIA Discovery Studio version 2017 R2 on the crystal structure of FGF23 (PDB: 5W21) reported by Chen et al (PDB: 5W21) 14 to compute solvent accessibility. Residues with relative solvent accessibility (RSA) more than 20% of maximum RSA within the structure were designated as solvent exposed residues, consistent with published studies 12 , 15 . In total, we selected fifteen solvent exposed FGF23 residues that covered every sub-domain of FGF23.…”

“…The second category consists of data-driven docking algorithms that make use of predicted or experimentally determined epitope and paratope constraints to guide the search process. For example, Tit-oon et al employed a knowledge-based strategy to guide alanine scanning and computational docking, which led to the accurate prediction of an antigen-antibody interface 12 . Cannon et al used experimental alanine scanning to optimize computational docking for in-silico affinity maturation of a high affinity antibody 13 .…”

Complexity of Viral Epitope Surfaces as Evasive Targets for Vaccines and Therapeutic Antibodies

“…We therefore leveraged a set of computational methods to model the NiV glycoprotein epitope bound by m102.4, and then select likely epitope and paratope hotspots for subsequent experimental investigation (92). These computational tools included homology modeling via ABodyBuilder (123), surface accessibility analysis, and significant interaction networks (91).…”

“…Specifically, we present examples of network and structure-based analyses of complex viral epitope surfaces from the standpoint of improving design and repurposing of therapeutic antibodies and mapping antigenic drift, as performed by us and others. These approaches include functional characterization of a cross-neutralizing Henipavirus antibody (92), developing a framework for antibody-glycan interactions (63), modeling N-glycan topology toward repurposing the antibody 2G12 (93), mapping antigenic orthogonality between and within overlapping RBD epitopes (51), and rapidly mapping the mutational landscape of the Omicron sub-variants (52,81).…”

Piperazine-substituted derivatives of favipiravir for Nipah virus inhibition: What do in silico studies unravel?

“…The structure of NiV with glycoprotein (G) attachment has 602 amino acid residues where the glycoprotein functions as a receptor-binding protein providing attachment to host cell receptors. This protein plays a vital role in facilitating the fusion of cell membrane with the virus through F protein by interacting with Ephirin-B2 receptors present on host cell and thereby making it an effective target for inhibition [9][10][11][12]. The World Health Organization (WHO) has set NiV as a priority disease on the WHO R&D Blueprint [3].…”