Residual Interactions of LL-37 with POPC and POPE:POPG Bilayer Model Studied by All-Atom Molecular Dynamics
Muhammad Yusuf1, Wanda Destiarani2, Ade Rizqi Ridwan Firdaus2
1Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Bandung 45363, Indonesia.
Abstract:
LL-37 is a membrane-active antimicrobial peptide (AMP) that could disrupt the integrity of bacterial membranes due to its inherent cationic and amphipathic nature. Developing a shorter derivative of a long peptide such as LL-37 is of great interest, as it can reduce production costs and cytotoxicity. However, more detailed information about the residual interaction between LL-37 and the membrane is required for further optimization. Previously, molecular dynamics simulation using mixed all-atom and united-atom force fields showed that LL-37 could penetrate the bilayer membrane. This study aimed to perform all-atom molecular dynamics simulations, highlighting the residual interaction of LL-37 with the simplest model of the bacterial membrane, POPE:POPG (2:1), and compare its interaction with the POPC, which represents the eukaryotic membrane. The result showed leucine-leucine as the leading residues of LL-37 that first contact the membrane surface. Then, the cationic peptide of LL-37 started to penetrate the membrane by developing salt bridges between positively charged amino acids, Lys-Arg, and the exposed phosphate group of POPE:POPG, which is shielded in POPC. Residues 18 to 29 are suggested as the core region of LL-37, as they actively interact with the POPE:POPG membrane, not POPC. These results could provide a basis for modifying the amino acid sequence of LL-37 and developing a more efficient design for LL-37 derivatives.
Insights
Antimicrobial peptide LL-37 interacts with bacterial membranes via specific residues, forming salt bridges. This interaction, particularly in residues 18-29, guides the design of more effective LL-37 derivatives.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- LL-37 is a potent antimicrobial peptide (AMP) with potential for bacterial membrane disruption.
- Shorter LL-37 derivatives offer reduced costs and cytotoxicity, but require detailed interaction knowledge.
- Previous simulations indicated LL-37 can penetrate lipid bilayers.
Purpose of the Study:
- To elucidate the detailed residual interactions of LL-37 with bacterial (POPE:POPG) and eukaryotic (POPC) membrane models.
- To identify key LL-37 residues involved in membrane interaction for derivative design.
- To compare LL-37's interaction mechanisms with bacterial versus eukaryotic membranes.
Main Methods:
- All-atom molecular dynamics simulations were employed.
- Simulations utilized a simplified bacterial membrane model (POPE:POPG, 2:1) and a eukaryotic model (POPC).
- Analysis focused on residue-level interactions and salt bridge formation.
Main Results:
- Leucine-leucine residues were identified as the initial contact points with the membrane surface.
- Cationic residues (Lys-Arg) formed salt bridges with POPE:POPG phosphate groups, facilitating penetration.
- Eukaryotic POPC membranes showed shielded phosphate groups, hindering LL-37 penetration compared to bacterial membranes.
- Residues 18-29 of LL-37 were identified as a core interaction region with the bacterial membrane model.
Conclusions:
- LL-37's interaction with bacterial membranes is mediated by specific residues and salt bridge formation.
- The core region (residues 18-29) is crucial for LL-37's selective interaction with bacterial membranes.
- These findings provide a foundation for rationally designing optimized LL-37 derivatives with enhanced efficacy and reduced side effects.
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