Charged Residue Implantation Improves the Affinity of a Cross-Reactive Dengue Virus Antibody

Author:

Wei HuilingORCID,Tan Jie,Zhou Bingjie,Guan Xiaotong,Zhong Qiaoxian,Wang JiaqiORCID

Abstract

Dengue virus (DENV) has four serotypes that complicate vaccine development. Envelope protein domain III (EDIII) of DENV is a promising target for therapeutic antibody development. One EDIII-specific antibody, dubbed 1A1D-2, cross-reacts with DENV 1, 2, and 3 but not 4. To improve the affinity of 1A1D-2, in this study, we analyzed the previously solved structure of 1A1D-2-DENV2 EDIII complex. Mutations were designed, including A54E and Y105R in the heavy chain, with charges complementary to the epitope. Molecular dynamics simulation was then used to validate the formation of predicted salt bridges. Interestingly, a surface plasmon resonance experiment showed that both mutations increased affinities of 1A1D-2 toward EDIII of DENV1, 2, and 3 regardless of their sequence variation. Results also revealed that A54E improved affinities through both a faster association and slower dissociation, whereas Y105R improved affinities through a slower dissociation. Further simulation suggested that the same mutants interacted with different residues in different serotypes. Remarkably, combination of the two mutations additively improved 1A1D-2 affinity by 8, 36, and 13-fold toward DENV1, 2, and 3, respectively. In summary, this study demonstrated the utility of tweaking antibody-antigen charge complementarity for affinity maturation and emphasized the complexity of improving antibody affinity toward multiple antigens.

Funder

National Natural Science Foundation of China

Major Projects of Guangdong Education Department for Foundation Research and Applied Re-search

Sun Yat-sen University

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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