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Molecular insights into the differential membrane targeting of maximin 1 in prokaryotic and eukaryotic cells

Jehoshaphat Oppong Mensah¹, Aaron Boakye¹, Michael Laryea¹

¹Department of Chemistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.

Journal of Biomolecular Structure & Dynamics

|December 12, 2023

Abstract:

Antimicrobial resistance is a pressing global health concern, underscoring the need for alternative treatments. Antimicrobial peptides (AMPs) have shown promise in this regard, with maximin 1 being a cationic, amphipathic AMP possessing antibacterial, antifungal, and antiviral activities with low hemolytic activity. In this study, we used molecular dynamics simulation to investigate the molecular basis for membrane selectivity of Maximin 1. By studying interactions between maximin 1 and different models of prokaryotic (anionic) and eukaryotic (zwitterionic) membranes, we found that Maximin 1 interacts more strongly with the prokaryotic membrane due to electrostatic attraction, while it weakly interacts with the zwitterionic eukaryotic membrane. Our simulations also revealed that Gly-1, Lys-5, Lys-11, Lys-15, and Lys-19 were identified to play a crucial role in the adsorption of maximin unto the prokaryotic membrane surface. The alpha-helical nature of the peptide, in addition to its amphipathic nature, was necessary for the adsorption of the peptide onto the surface of the prokaryotic membrane. Interestingly, the later transition of the alpha helix into a random coil was crucial in penetrating the prokaryotic membrane while hindering interactions with the eukaryotic membrane. Residues in the middle region of the peptide (residues 9-16) were also responsible for permeating the prokaryotic membrane over the eukaryotic membrane. These findings shed light on the peptide's selective targeting of bacterial membranes over human cell membranes and could inform the design of more effective AMPs.Communicated by Ramaswamy H. Sarma.

Insights

Antimicrobial peptides like Maximin 1 show promise against resistant microbes. Molecular dynamics reveal Maximin 1 selectively targets bacterial membranes over human cells, offering a basis for new drug design.

Area of Science:

Biochemistry
Molecular Biology
Computational Chemistry

Background:

Antimicrobial resistance (AMR) is a major global health threat, necessitating novel therapeutic strategies.
Antimicrobial peptides (AMPs) are a promising class of therapeutics with broad-spectrum activity and low toxicity.
Maximin 1 is a cationic, amphipathic AMP exhibiting antibacterial, antifungal, and antiviral properties with minimal hemolytic activity.

Purpose of the Study:

To elucidate the molecular mechanisms underlying the membrane selectivity of the antimicrobial peptide Maximin 1.
To investigate the interactions of Maximin 1 with both prokaryotic (bacterial) and eukaryotic (human) membrane models.
To identify key peptide residues and structural features responsible for selective membrane targeting.

Main Methods:

Utilized molecular dynamics (MD) simulations to model and analyze the behavior of Maximin 1.
Simulated interactions between Maximin 1 and distinct models representing anionic prokaryotic and zwitterionic eukaryotic membranes.
Analyzed peptide-membrane interactions, focusing on electrostatic forces, conformational changes, and residue-specific contributions.

Main Results:

Maximin 1 exhibited stronger electrostatic attraction and adsorption to anionic prokaryotic membranes compared to zwitterionic eukaryotic membranes.
Specific residues (Gly-1, Lys-5, Lys-11, Lys-15, Lys-19) and the peptide's alpha-helical, amphipathic structure were crucial for prokaryotic membrane adsorption.
A transition from alpha-helix to random coil in the peptide's middle region (residues 9-16) facilitated prokaryotic membrane penetration while limiting eukaryotic membrane interaction.

Conclusions:

Maximin 1 demonstrates inherent selectivity for bacterial membranes over human cell membranes, driven by electrostatic interactions and specific structural dynamics.
The findings provide a molecular understanding of Maximin 1's selective action, supporting its potential as a therapeutic agent.
This research can guide the rational design of novel antimicrobial peptides with enhanced efficacy and specificity for combating antimicrobial resistance.

Read full analysis

Keywords:

Antimicrobial resistance antimicrobial peptides area per lipid drug discovery hemolytic activity of peptides molecular dynamics simulations

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