Rational engineering of a human anti-dengue antibody through experimentally validated computational docking

Area of Science:

• Biochemistry
• Structural Biology
• Immunology

Background:

• Antibodies are crucial in research and biopharmaceuticals.
• Rational engineering of antibodies requires accurate structural data, often obtained via X-ray crystallography.
• High-resolution X-ray structures are not always feasible, necessitating alternative methods for antibody characterization.

Purpose of the Study:

• To investigate the structure of a human antibody in complex with Dengue virus serotypes.
• To develop and apply a method for rational antibody engineering without high-resolution X-ray structures.
• To improve antibody binding selectivity and neutralization efficacy against Dengue virus.

Main Methods:

• Solution Nuclear Magnetic Resonance (NMR) epitope mapping was employed to determine antibody binding sites.
• Computational docking was used to model the antibody-Dengue virus complex structure.
• Antibody mutants were designed based on the structural models derived from NMR and docking.

Main Results:

• The combined NMR epitope mapping and computational docking approach accurately modeled the antibody-Dengue virus complex.
• Rational design of antibody mutants led to predictable alterations in binding selectivity.
• Engineered antibody mutants demonstrated up to a 40-fold improvement in Dengue virus neutralization.

Conclusions:

• Combining experimental NMR epitope mapping with computational docking provides an accurate method for studying antibody-pathogen interactions.
• This approach enables successful rational engineering of antibodies, even without high-resolution X-ray structures.
• The developed strategy holds significant potential for advancing antibody-based therapeutics and diagnostics.