Ibalizumab-Human CD4 Receptor Interaction: Computational Alanine Scanning Molecular Dynamics Studies
Antibody drugs are used in the treatment of many chronic diseases. Recently, however, patients and doctors
have encountered problems with drug resistance, and improving the affinity of antibody drugs has therefore become a
pressing issue. Ibalizumab is a humanized monoclonal antibody that binds human CD4, the primary receptor for human
immunodeficiency virus type 1 (HIV-1). In this study, we sought to identify the key residues of the complementaritydetermining
regions (CDRs) of ibalizumab. Virtual alanine mutations (complementarity-determining regions of
ibalizumab) were also studied using solvated interaction energies derived from molecular dynamics and the explicit water
model. Using 1,000 nanosecond molecular dynamic simulations, we identified six residues: Tyr50 [HCDR2], Tyr53
[HCDR3], Asp58 [HCDR2], Glu95 [HCDR2], and Arg95 [LCDR3]. The Robetta alanine-scanning mutagenesis method
and crystallographic information were used to verify our simulations. Our simulated binding affinity of −17.33 kcal/mol is
close to the experimentally determined value of −16.48 kcal/mol. Our findings may be useful for protein engineering the
structure of the ibalizumab-human CD4 receptor complex. Moreover, the six residues that we identified may play a
significant role in the development of bioactive antibody analogues.
Keywords: Antibody drugs, drug resistance, human immunodeficiency virus type 1 (HIV-1), Ibalizumab, molecular dynamics,
Robetta alanine-scanning mutagenesis method.
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