National Academy of Agricultural Sciences (NAAS)
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PRINT ISSN : 2319-7692
Online ISSN : 2319-7706 Issues : 12 per year Publisher : Excellent Publishers Email : editorijcmas@gmail.com / submit@ijcmas.com Editor-in-chief: Dr.M.Prakash Index Copernicus ICV 2018: 95.39 NAAS RATING 2020: 5.38 |
The emergence of multidrug-resistant Gram-negative bacteria underscores the need for antibiotics with novel mechanisms of action. The essential β-barrel assembly machinery (BAM) complex, which is crucial for the biogenesis of outer membrane proteins (OMPs), represents as a promising therapeutic target. In this study, we investigate the potential role of CaNCR63, a nodule-specific cysteine-rich (NCR) peptide derived from chickpea (Cicer arietinum), as a novel inhibitor of BamA complex. Using a multi-step computational approach, we confirmed CaNCR63’s antimicrobial peptide-like physicochemical characteristics and the presence of a conserved γ-core motif, justifying its selection. Comparative molecular docking between CaNCR63 and darobactin against the E. coli BAM complex showed a high-affinity binding configuration for CaNCR63 at the functionally significant lateral gate of BamA, a site also targeted by the known antibiotic darobactin. To validate this static model, a 100 ns all-atom molecular dynamics simulation of the CaNCR63-BamA complex within a model bacterial membrane was conducted. The simulation verified the formation of a dynamically stable complex, marked by a persistent network of intermolecular contacts and hydrogen bonds. Binding free energy calculations (MM/PBSA) suggested a strong, sub-nanomolar binding affinity (?Gbind = -12.75 kcal/mol), predominantly driven by electrostatic interactions. Additionally, analysis of system’s dynamics showed that CaNCR63 binding allosterically modulates the flexibility of the entire BAM complex, limiting the conformational plasticity of the lateral gate. Collectively, these findings provide a cohesive, multi-scale model suggesting that CaNCR63 functions as a darobactinlike inhibitor by physically locking the lateral gate, thereby impeding the OMP assembly process. This research supports the potential of plant-derived NCR peptides as a promising chemical framework for developing new antibiotics targeting Gram-negative pathogens.
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