Molecular dynamics simulation of the membrane binding and disruption mechanisms by antimicrobial scorpion
José-Luis Velasco-Bolom1, Gerardo Corzo2, Ramón Garduño-Juárez1
1a Instituto de Ciencias Físicas , Universidad Nacional Autónoma de México , Cuernavaca , Morelos 62210 , México.
Abstract:
Pandinin 2 (Pin2) is an alpha-helical polycationic peptide, identified and characterized from venom of the African scorpion Pandinus imperator with high antimicrobial activity against Gram-positive bacteria and less active against Gram-negative bacteria, however it has demonstrated strong hemolytic activity against sheep red blood cells. In the chemically synthesized Pin2GVG analog, the GVG motif grants it low hemolytic activity while keeping its antimicrobial activity. In this work, we performed 12 μs all-atom molecular dynamics simulation of the antimicrobial peptides (AMPs) Pin2 and Pin2GVG to explore their adsorption mechanism and the role of their constituent amino acid residues when interacting with pure POPC and pure POPG membrane bilayers. Starting from an α-helical conformation, both AMPs are attracted at different rates to the POPC and POPG bilayer surfaces due to the electrostatic interaction between the positively charged amino acid residues and the charged moieties of the membranes. Since POPG is an anionic membrane, the PAMs adhesion is stronger to the POPG membrane than to the POPC membrane and they are stabilized more rapidly. This study reveals that, before the insertion begins, Pin2 and Pin2GVG remained partially folded in the POPC surface during the first 300 and 600 ns, respectively, while they are mostly unfolded in the POPG surface during most of the simulation time. The unfolded structures provide for a large number of intermolecular hydrogen bonds and stronger electrostatic interactions with the POPG surface. The results show that the aromatic residues at the N-terminus of Pin2 initiate the insertion process in both POPC and POPG bilayers. As for Pin2GVG in POPC the C-terminus residues seem to initiate the insertion process while in POPG this process seems to be slowed down due to a strong electrostatic attraction. The membrane conformational effects upon PAMs binding are measured in terms of the area per lipid and the contact surface area. Several replicas of the systems lead to the same observations.
Insights
Antimicrobial peptides (AMPs) Pin2 and Pin2GVG interact differently with membrane bilayers. Pin2GVG shows reduced hemolytic activity while retaining antimicrobial properties, with distinct adsorption and insertion mechanisms observed in POPC and POPG membranes.
Area of Science:
- Biophysics
- Computational Biology
- Biochemistry
Background:
- Pandinin 2 (Pin2) is a scorpion-derived antimicrobial peptide (AMP) with potent activity against Gram-positive bacteria but also exhibits hemolytic activity.
- A synthesized analog, Pin2GVG, retains antimicrobial efficacy while significantly reducing hemolytic activity through a GVG motif.
- Understanding the interaction mechanisms of AMPs with lipid bilayers is crucial for developing new antimicrobial agents.
Purpose of the Study:
- To investigate the adsorption and insertion mechanisms of the antimicrobial peptides (AMPs) Pin2 and Pin2GVG.
- To explore the role of specific amino acid residues in AMP-membrane interactions.
- To compare the behavior of Pin2 and Pin2GVG on different membrane compositions (POPC and POPG).
Main Methods:
- All-atom molecular dynamics simulations of 12 μs were performed for Pin2 and Pin2GVG.
- Simulations involved interactions with pure 1,2-dioleoyl-sn-glycero-3-phosphocholine (POPC) and 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1'-glycerol) (POPG) membrane bilayers.
- Analysis included adsorption rates, structural changes (folding/unfolding), hydrogen bonding, electrostatic interactions, and membrane conformational effects (area per lipid, contact surface area).
Main Results:
- Both AMPs adsorb to POPC and POPG bilayers via electrostatic interactions, with stronger and faster adhesion to the anionic POPG membrane.
- Pin2 and Pin2GVG exhibit distinct behaviors on the membrane surfaces: partial unfolding on POPC and significant unfolding on POPG.
- Aromatic residues at the N-terminus of Pin2 initiate insertion into both membranes, while Pin2GVG's insertion into POPC is initiated by C-terminus residues, and slowed by electrostatic attraction in POPG.
Conclusions:
- The GVG motif in Pin2GVG modulates its interaction with lipid bilayers, reducing hemolytic activity while maintaining antimicrobial function.
- Membrane charge significantly influences AMP adsorption and structural dynamics, with anionic POPG promoting unfolding and stronger interactions.
- The study elucidates the molecular mechanisms underlying AMP-membrane interactions, providing insights for the rational design of safer and more effective antimicrobial peptides.
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