Key result
An in silico designed variant of mAb 4C4 with five specific mutations demonstrated better binding affinities towards synthetic and natural G-H loops of FMDV-VP1 than wild-type 4C4 and SD6.
In silico mutagenesis identified a variant of mAb 4C4 with improved binding affinity to FMDV, suggesting potential as an antibody-based therapeutic for foot and mouth disease.
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Hypothesis-generating for FMDV mAb engineering; requires experimental validation before any therapeutic consideration.
Investigating the behaviour of bio-molecules through computational mutagenesis is gaining interest to facilitate the development of new therapeutic solutions for infectious diseases. The antigenetically variant genotypes of foot and mouth disease virus (FMDV) and their subsequent infections are challenging to tackle with traditional vaccination. In such scenario, neutralizing antibodies might provide an alternate solution to manage the FMDV infection. Thus, we have analysed the interaction of the mAb 4C4 with a synthetic G-H loop of FMDV-VP1 through in silico mutagenesis and molecular modelling. Initially, a set of 25,434 mutants were designed and the mutants having better energetic stability than 4C4 were clustered based on sequence identity. The best mutant representing each cluster was selected and evaluated for its binding affinity with the antigen in terms of docking scores, interaction energy and binding energy. Six mutants have confirmed better binding affinities towards the antigen than 4C4. Further, interaction of these mutants with the natural G-H loop that is bound to mAb SD6 was also evaluated. One 4C4 variant having mutations at the positions 2034(N→L), 2096(N→C), 2098(D→Y), 2532(T→K) and 2599(A→G) has revealed better binding affinities towards both the synthetic and natural G-H loops than 4C4 and SD6, respectively. A molecular dynamic simulation for 50 ns was conducted for mutant and wild-type antibody structures which supported the pre-simulation results. Therefore, these mutations on mAb 4C4 are believed to provide a better antibody-based therapeutic option for FMD. Communicated by Ramaswamy H. Sarma.
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Sahu et al. (2018) studied Foot and mouth disease. Mutated mAb 4C4 variants vs. Wild-type mAb 4C4 and SD6 was evaluated on Binding affinity with the antigen (docking scores, interaction energy, and binding energy). An in silico designed variant of mAb 4C4 with five specific mutations demonstrated better binding affinities towards synthetic and natural G-H loops of FMDV-VP1 than wild-type 4C4 and SD6.
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