Accelerated molecular dynamics simulation analysis of MSI-594 in a lipid bilayer
Shruti Mukherjee1, Rajiv K Kar1, Ravi Prakash Reddy Nanga2
1Department of Biophysics, Bose Institute, P-1/12 CIT Scheme VII (M), Kolkata 700 054, India. anirbanbhunia@gmail.com bhunia@jcbose.ac.in.
Abstract:
Multidrug resistance against the existing antibiotics is one of the most challenging threats across the globe. Antimicrobial peptides (AMPs), in this regard, are considered to be one of the effective alternatives that can overcome bacterial resistance. MSI-594, a 24-residue linear alpha-helical cationic AMP, has been shown to function via the carpet mechanism to disrupt bacterial membrane systems. To better understand the role of lipid composition in the function of MSI-594, in the present study, eight different model membrane systems have been studied using accelerated molecular dynamics (aMD) simulations. The simulated results are helpful in discriminating the particular effects of cationic MSI-594 against zwitterionic POPC, anionic POPG and POPS, and neutral POPE lipid moieties. Additionally, the effects of various heterogeneous POPC/POPG (7 : 3), POPC/POPS (7 : 3), and POPG/POPE (1 : 3 and 3 : 1) bilayer systems on the dynamic interaction of MSI-594 have also been investigated. The effect on the lipid bilayer due to the interaction with the peptide is characterized by lipid acyl-chain order, membrane thickness, and acyl-chain dynamics. Our simulation results show that the lipid composition affects the membrane interaction of MSI-594, suggesting that membrane selectivity is crucial to its mechanism of action. The results reported in this study are helpful to obtain accurate atomistic-level information governing MSI-594 and its membrane disruptive antimicrobial mechanism of action, and to design next generation potent antimicrobial peptides.
Insights
Antimicrobial peptides (AMPs) like MSI-594 combat antibiotic resistance by disrupting bacterial membranes. This study uses simulations to show how lipid composition influences MSI-594
Area of Science:
- Biophysics
- Computational Chemistry
- Molecular Biology
Background:
- Multidrug resistance is a global health threat.
- Antimicrobial peptides (AMPs) offer a promising alternative to conventional antibiotics.
- MSI-594 is a cationic AMP that disrupts bacterial membranes via the carpet mechanism.
Purpose of the Study:
- To investigate the influence of lipid composition on the antimicrobial activity of MSI-594.
- To elucidate the atomistic-level interactions between MSI-594 and various model membrane systems.
- To provide insights for designing next-generation antimicrobial peptides.
Main Methods:
- Accelerated molecular dynamics (aMD) simulations were employed.
- Eight different model membrane systems with varying lipid compositions were simulated.
- Interactions were analyzed by characterizing lipid acyl-chain order, membrane thickness, and acyl-chain dynamics.
Main Results:
- The lipid composition significantly affects the interaction of MSI-594 with model membranes.
- MSI-594 exhibits distinct interactions with zwitterionic, anionic, and neutral lipid moieties.
- Heterogeneous lipid bilayers modulate the dynamic interaction of MSI-594.
Conclusions:
- Membrane selectivity is crucial for the antimicrobial mechanism of MSI-594.
- Understanding lipid-peptide interactions is key to developing effective AMPs.
- This study provides atomistic insights into MSI-594's membrane disruption mechanism.
