Molecular Dynamics Simulation of the Interaction of Two Linear Battacin Analogs with Model Gram-Positive and Gram-Negative Bacterial Cell Membranes

Abstract

Antimicrobial peptides (AMPs) are a potential solution to the increasing threat of antibiotic resistance, but successful design of active but nontoxic AMPs requires understanding their mechanism of action. Molecular dynamics (MD) simulations can provide atomic-level information regarding how AMPs interact with the cell membrane. Here, we have used MD simulations to study two linear analogs of battacin, a naturally occurring cyclic, lipidated, nonribosomal AMP. Like battacin, these analogs are active against Gram-negative multidrug resistant and Gram-positive bacteria, but they are less toxic than battacin. Our simulations show that this activity depends upon a combination of positively charged and hydrophobic moieties. Favorable interactions with negatively charged membrane lipid head groups drive association with the membrane and insertion of hydrophobic residues, and the Nterminal lipid anchors the peptides to the membrane surface. Both effects are required for stable membrane binding.

Co-crystals of ethenzamide with 2-nitrobenzoic acid - Conformational analysis, MD simulations and DFT investigations

“…Research on subjects of crystal engineering and supra molecular synthesis of cocrystals is large and growing [33,34]. In order to complement these themes, we would like to discuss the preliminary actions that should be addressed (before any reaction take place!)…”

“…when aiming to maximize the experimental e cacy of developing co-crystalline materials. The FDA de nes co-crystals as "crystalline materials composed of two or more different molecules, typically active pharmaceutical ingredient (API) and cocrystal formers ('coformers'), in the same crystal lattice" [34]. Co-crystallization is a promising method for modifying and improving an API's physicochemical properties without causing covalent modi cations to the drug molecule.…”

Anionic Lipid Clustering-Mediated Bactericidal Activity and Selective Toxicity of Quaternary Ammonium-Substituted Polycationic Pullulan against the Staphylococcus aureus Bacterial Membrane

“…Here, we have investigated the molecular interactions between CP4 and a Gram-positive ( Staphylococcus aureus ) bacterial membrane as an attempt to unravel their antibacterial functioning through systematic atomistic MD simulations. Contrary to the Gram-negative bacteria, the studied S. aureus membrane is a heterogeneous bilayer composed of anionic and cationic lipids and lacks zwitterionic lipids. − However, the overall charge on the membrane surface remains negative, thus enabling it to respond strongly to cationic polymers through electrostatic interactions. We have focused on the structural changes induced in the membrane upon application of CP4 tetramers with a strong emphasis on the lateral lipid organization.…”

Identification of Bacterial Membrane Selectivity of Romo1-Derived Antimicrobial Peptide AMPR-22 via Molecular Dynamics

“…LL-37, which is derived from the human cathelicidin family, was shown to preferentially bind POPG (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol), mimicking bacterial membranes, over POPC (1palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), mimicking mammalian membranes [24]. MD simulations of two battacin analogs, whose toxicity is attenuated compared to the parent, showed how the positively charged amino acids and hydrophobic moieties play a role in the interaction with the inner membrane of S. aureus or that of E. coli [25]. MD simulation has become a fascinating tool to understand how AMPs act at the atomic level with a multi-scale view of a fundamental biophysical process (e.g., the complex interplay between AMPs and membrane, and what amino acids are involved in the membrane affinity) [26] as the computational power increases.…”