Ibalizumab-human CD4 receptor interaction: computational alanine scanning molecular dynamics studies.

Area of Science:

• Biochemistry
• Immunology
• Structural Biology

Background:

• Antibody drugs are vital for chronic disease treatment.
• Drug resistance and suboptimal affinity are significant clinical challenges.
• Ibalizumab, a monoclonal antibody, targets the CD4 receptor for HIV-1 therapy.

Purpose of the Study:

• To identify critical amino acid residues in the complementarity-determining regions (CDRs) of ibalizumab.
• To understand the molecular basis of ibalizumab's binding affinity to the CD4 receptor.
• To provide insights for protein engineering of antibody drugs.

Main Methods:

• Virtual alanine scanning mutagenesis using molecular dynamics simulations.
• Calculation of solvated interaction energies with an explicit water model.
• Validation of simulation results using the Robetta alanine-scanning method and crystallographic data.

Main Results:

• Six key residues in ibalizumab's CDRs were identified: Tyr50 (HCDR2), Tyr53 (HCDR3), Asp58 (HCDR2), Glu95 (HCDR2), and Arg95 (LCDR3).
• Simulated binding affinity (-17.33 kcal/mol) closely matched experimental values (-16.48 kcal/mol).
• Identified residues are critical for the ibalizumab-CD4 interaction.

Conclusions:

• The study successfully pinpointed critical residues governing ibalizumab-CD4 binding affinity.
• These findings are valuable for protein engineering and enhancing antibody drug efficacy.
• The identified residues offer targets for developing novel bioactive antibody analogues.