Computational-guided determination of the functional role of 447-52D long CDRH3

Author:

Kamau Edwin1,Bonneau Richard23,Kong Xiang-Peng1

Affiliation:

1. Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York NY, USA

2. Department of Biology, Center for Genomics and Systems Biology and Computer Science Department, Courant Institute of Mathematical Sciences, New York University, New York NY, USA

3. Center for Computational Biology, Flatiron Institute, New York NY, USA

Abstract

Abstract447-52D (447) is a human monoclonal antibody that recognizes a conserved epitope in the crown region of the third variable loop (V3) of HIV-1 gp120, and like many anti-HIV-1 antibodies with broad neutralization capabilities, it has a long heavy-chain complementarity determining region (CDRH3). Here, we use a combination of computational mutagenesis and modeling in tandem with fluorescence polarization assays to interrogate the molecular basis of 447 CDRH3 length and the individual contribution of selected CDRH3 residues to affinity. We observe that 447 CDRH3 length provides a large binding surface area and the best enthalpic contributions derived from hydrophobic packing, main-chain hydrogen bonds, electrostatic and van der Waals interactions. We also found out that CDRH3 residue Try100I is critical to 447 binding affinity.

Funder

NIH

Publisher

Oxford University Press (OUP)

Subject

Molecular Biology,Biochemistry,Bioengineering,Biotechnology

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