Hydrophobic Residues Confer the Helicity and Membrane Permeability of Ocellatin-1 Antimicrobial Peptide Scaffold Towards Therapeutics

Antimicrobial peptides (AMPs) are persisting in all living organisms as evolutionarily conserved inherent components of the innate immune system. Due to relatively lower microbial drug resistance, AMPs can act as efficient small molecule based drugs. Among which, Ocellatin-1 (O1) AMP, extracted from South American frog Leptodactylus ocellatus poses greater restorative competence against pathogens. Analyses of the key amino acid residues in O1 AMP have suggested vital properties linked to the maintenance of its structural stability and the functional activity. To distinguish the contribution of side chains in each residue that facilitates its pharmacodynamics characteristics, we combined molecular simulation and computational Alanine Scanning Mutagenesis (cASM). This approach explores the alanine substituted analogues in comparison with native O1 peptide, we identified at sequence analysis, conformational sampling and membrane simulation. We observed isoleucine at 5th position and leucine at 14th position to be crucial for the therapeutic scaffold of O1 AMP. In conclusion, the role of individual residues in O1 AMP scaffold remains rationale behind maintaining its structural integrity and therefore its therapeutic potential; this therapeutic scaffold will need to be considered in future studies of membranolytic O1 peptide-based drug discovery.

Automated summary

Antimicrobial peptides (AMPs) are evolutionarily conserved components of the innate immune system found in all living organisms. Due to their relatively lower microbial drug resistance, AMPs can serve as efficient small molecule drugs. Ocellatin-1 (O1) AMP from the South American frog Leptodactylus ocellatus shows greater efficacy against pathogens due to its unique amino acid residues contributing to its structural stability and functional activity. By analyzing the key residues in O1 AMP, it was found that specific residues like isoleucine and leucine are crucial for maintaining its therapeutic scaffold. Additionally, molecular simulation and computational analysis further confirmed the importance of these residues in O1 AMP for potential drug discovery applications.