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The Mechanism of Action of SAAP-148 Antimicrobial Peptide as Studied with NMR and Molecular Dynamics Simulations
Morgane Adélaïde1, Evgeniy Salnikov2, Francisco Ramos-Martín1
1Unité de Génie Enzymatique et Cellulaire UMR 7025 CNRS, Université de Picardie Jules Verne, 80039 Amiens, France.
Background:
SAAP-148 is an antimicrobial peptide derived from LL-37. It exhibits excellent activity against drug-resistant bacteria and biofilms while resisting degradation in physiological conditions. Despite its optimal pharmacological properties, its mechanism of action at the molecular level has not been explored.
Methods:
The structural properties of SAAP-148 and its interaction with phospholipid membranes mimicking mammalian and bacterial cells were studied using liquid and solid-state NMR spectroscopy as well as molecular dynamics simulations.
Results:
SAAP-148 is partially structured in solution and stabilizes its helical conformation when interacting with DPC micelles. The orientation of the helix within the micelles was defined by paramagnetic relaxation enhancements and found similar to that obtained using solid-state NMR, where the tilt and pitch angles were determined based on 15N chemical shift in oriented models of bacterial membranes (POPE/POPG). Molecular dynamic simulations revealed that SAAP-148 approaches the bacterial membrane by forming salt bridges between lysine and arginine residues and lipid phosphate groups while interacting minimally with mammalian models containing POPC and cholesterol.
Conclusions:
SAAP-148 stabilizes its helical fold onto bacterial-like membranes, placing its helix axis almost perpendicular to the surface normal, thus probably acting by a carpet-like mechanism on the bacterial membrane rather than forming well-defined pores.
Insights
SAAP-148, an antimicrobial peptide, stabilizes its helical structure on bacterial membranes. This suggests a carpet-like mechanism, differentiating it from pore formation, for combating drug-resistant bacteria.
Area of Science:
- Biochemistry
- Molecular Biology
- Antimicrobial Peptides
Background:
- SAAP-148 is a potent antimicrobial peptide derived from LL-37.
- It demonstrates significant activity against drug-resistant bacteria and biofilms.
- Its molecular-level mechanism of action remained unexplored despite favorable properties.
Purpose of the Study:
- To elucidate the molecular mechanism of action of SAAP-148.
- To investigate the structural properties and membrane interactions of SAAP-148.
Main Methods:
- Utilized liquid and solid-state NMR spectroscopy.
- Employed molecular dynamics simulations.
- Studied interactions with phospholipid membranes mimicking bacterial and mammalian cells.
Main Results:
- SAAP-148 adopts a helical conformation upon interaction with bacterial membranes.
- NMR and simulations revealed specific orientation and tilt angles within bacterial membranes.
- Molecular dynamics showed SAAP-148 forms salt bridges with bacterial lipids and minimal interaction with mammalian lipids.
Conclusions:
- SAAP-148 stabilizes a helical fold on bacterial membranes, oriented nearly perpendicular to the surface.
- The mechanism likely involves a carpet-like disruption of the bacterial membrane.
- This contrasts with pore-forming mechanisms, offering insights into its antimicrobial action.
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