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Computational evaluation of modified peptides from human neutrophil peptide 1 (HNP-1)
Neda Moazzezy1, Elham Rismani2, Maryam Rezaei1
1Molecular Biology Department, Pasteur Institute of Iran, Tehran, Iran.
Abstract:
The development of bacterial resistance toward antibiotics has been led to pay attention to the antimicrobial peptides (AMPs). The common mechanism of AMPs is disrupting the integrity of the bacterial membrane. One of the most accessible targets for α-defensins human neutrophil peptide-1 (HNP-1) is lipid II. In the present study, we performed homology modeling and geometrical validation of human neutrophil defensin 1. Then, the conformational and physicochemical properties of HNP-1 derived peptides 2Abz14S29, 2Abz23S29, and HNP1ΔC18A, as well as their interaction with lipid II were studied computationally. The overall quality of the predicted model of full protein was -5.14, where over 90% of residues were in the most favored and allowed regions in the Ramachandran plot. Although HNP-1 and HNP1ΔC18A were classified as unstable peptides, 2Abz14S29 and 2Abz23S29 were stable, based on the instability index values. Molecular docking showed similar interaction pattern of peptides and HNP-1 to lipid II. Molecular dynamic simulations revealed the overall stability of conformations, though the fluctuations of amino acids in the modified peptides were relatively higher than HNP-1. Further, the binding affinity constant (Kd) of HNP-1 and 2Abz23S29 in complex with lipid II was 10 times stronger than 2Abz14S29 and HNP1ΔC18A. Overall, computational studies of conformational and interaction patterns have signified how derived peptides could have displayed relatively similar antimicrobial results compared to HNP-1 in the reported experimental studies. Chemical modifications not only have improved the physicochemical properties of derived peptides compared to HNP-1, but also they have retained the similar pattern and binding affinity of peptides. Communicated by Ramaswamy H. Sarma.
Insights
Antimicrobial peptides (AMPs) combat antibiotic resistance by disrupting bacterial membranes. Modified human neutrophil peptide-1 (HNP-1) derivatives showed stable properties and similar interactions with lipid II, suggesting potential antimicrobial efficacy.
Area of Science:
- Biochemistry
- Computational Biology
- Drug Discovery
Background:
- Rising antibiotic resistance necessitates novel antimicrobial strategies.
- Antimicrobial peptides (AMPs), like human neutrophil peptide-1 (HNP-1), disrupt bacterial membranes.
- Lipid II is a key target for AMPs, including HNP-1.
Purpose of the Study:
- To computationally investigate the conformational and physicochemical properties of HNP-1 derived peptides.
- To analyze the interaction patterns of these modified peptides with Lipid II.
- To assess the potential of modified peptides as alternatives to native HNP-1.
Main Methods:
- Homology modeling and geometrical validation of HNP-1.
- Computational analysis of derived peptides (2Abz14S29, 2Abz23S29, HNP1ΔC18A) including stability and physicochemical properties.
- Molecular docking and molecular dynamic simulations to study interactions with Lipid II.
Main Results:
- Modified peptides 2Abz14S29 and 2Abz23S29 exhibited enhanced stability compared to HNP-1 and HNP1ΔC18A.
- All studied peptides showed similar interaction patterns with Lipid II.
- Binding affinity (Kd) for HNP-1 and 2Abz23S29 was significantly stronger than for 2Abz14S29 and HNP1ΔC18A.
Conclusions:
- Computational studies indicate that chemically modified HNP-1 derivatives can retain antimicrobial activity.
- Modifications improved physicochemical properties while maintaining essential interaction mechanisms with Lipid II.
- These findings support the development of novel AMPs derived from HNP-1 for combating bacterial infections.
