Decoding the Structure-Function Correlation of Adeno-Associated Virus 2 Capsid Mutants Recognition by A20 Antibody: A...

Area of Science:

• Molecular biology
• Biophysics
• Gene therapy

Background:

• Adeno-associated virus serotype 2 (AAV2) is a key gene therapy vector.
• Pre-existing immunity against AAV2 limits its therapeutic efficacy.
• Understanding capsid-antibody interactions is crucial for developing improved vectors.

Purpose of the Study:

• To investigate the structural dynamics of AAV2 capsid variants interacting with an antibody (A20).
• To identify key interaction sites and mechanisms governing capsid-antibody recognition.
• To develop a predictive model for designing AAV2 variants with reduced immunogenicity.

Main Methods:

• Coarse-grained elastic network molecular dynamics simulations.
• Analysis of structural descriptors (RMSD, Rg, SASA, COM distances, contact probabilities).
• Per-residue energy decomposition and multiple linear regression modeling.

Main Results:

• Identified critical interactions involving three capsid subunits and antibody heavy-chain CDRs.
• Pinpointed key interaction hotspots correlating with experimental neutralization data.
• Developed a predictive model (R^2=0.949) linking structural changes to binding affinity reduction.

Conclusions:

• Mechanistic insights into AAV2 capsid-antibody recognition were gained.
• A structure-guided framework for designing less immunogenic AAV2 variants was established.
• This approach advances the development of next-generation gene therapy vectors.