Structure and Dynamics of Cinnamycin–Lipid Complexes: Mechanisms of Selectivity for Phosphatidylethanolamine Lipids

Abstract

Cinnamycin is a lantibiotic peptide, which selectively binds to and permeabilizes membranes containing phosphatidylethanolamine (PE) lipids. As PE is a major component of many bacterial cell membranes, cinnamycin has considerable potential for destroying these. In this study, molecular dynamics simulations are used to elucidate the structure of a lipid–cinnamycin complex and the origin of selective lipid binding. The simulations reveal that cinnamycin selectively binds to PE by forming an extensive hydrogen-bonding network involving all three hydrogen atoms of the primary ammonium group of the PE head group. The substitution of a single hydrogen atom with a methyl group on the ammonium nitrogen destabilizes this hydrogen-bonding network. In addition to binding the primary ammonium group, cinnamycin also interacts with the phosphate group of the lipid through a previously uncharacterized phosphate-binding site formed by the backbone Phe10-Abu11-Phe12-Val13 moieties (Abu = 1-α-aminobutyric acid). In addition, hydroxylation of Asp15 at Cβ plays a role in selective binding of PE due to its tight interaction with the charged amine of the lipid head group. The simulations reveal that the position and orientation of the peptide in the membrane depend on the type of lipid to which it binds, suggesting a reason for why cinnamycin selectively permeabilizes PE-containing membranes.

Understanding the Mechanism of Action of NAI-112, a Lanthipeptide with Potent Antinociceptive Activity

“…Class II lantibiotics, such as mersacidin and actagardin, also bind to lipid II [28]. Interestingly, some structurally unrelated class II lantibiotics, namely cinnamycin and its variants duramycin and ancovenin, have been shown to bind to phosphatidylethanolamine-containing lipids [29][30][31][32]. Two-peptide lantibiotics, exemplified by lacticin 3147, also form a complex with lipid II through their mersacidin-like component [33].…”

Mining and Biosynthesis of Bioactive Lanthipeptides From Microorganisms

“…For instance, microbisporicin, NAI-107, mersacidin and penisin exhibit inhibition against antibiotic-resistant pathogens, such as methicillin-resistant Staphylococcus aureus ( Baindara et al, 2018 ). Cinnamycin could kill Bacillus and also has antifungal ability ( Chen et al, 2017 ; Vestergaard et al, 2019 ). Cebulantin is effective against the growth of various Vibrio pathogens ( Moon et al, 2019 ).…”

“…Cinnamycin with bactericidal activity can target the primary amino group of phosphatidylethanolamine on the bacterial cell membrane to form a hydrogen-bonding complex. This complex could also specifically bind to the phosphate group of phosphatidylethanolamines ( Vestergaard et al, 2019 ). Since the expression of phosphatidylethanolamines on the inner and outer surfaces of tumor cell membranes is abnormally abundant, mathermycin is able to interfere with the metabolic activity of tumor cells and induce tumor cell necrosis by targeting phosphatidylethanolamines ( Cheng et al, 2021 ; van Staden et al, 2021 ).…”

Implication of Mini Project Organic Chemistry Experiments for Improving Organic Chemistry Concept

“…Penamaan karbohidrat berasal dari istilah "hidrat dari karbon", hal ini karena rumus umumnya adalah C n (H 2 O) m . Tetapi seiring dengan perkembangan ilmu pengetahuan, diketahui bahwa sebenarnya karbohidrat bukanlah hidrat dari karbon, namun merupakan polihidroksi aldehida atau polihidroksi keton; 5) Lipida (Olżyńska et al, 2020;Vestergaard et al, 2019), lipida biasanya tersusun atas asam lemak, gliserol, dan suatu gugus bermuatan seperti fosfat. Secara garis besar, lipida diklasifikasikan menjadi 2 golongan yaitu lipida sederhana yakni lipida yang terdiri dari asam-asam lemak dan alcohol dan ipida majemuk, yaitu ester dari gliserol dan asam lemak yang memiliki gugusgugus lain selain asam lemak; 5) Protein (Lin et al, 2020;Piana et al, 2020), protein merupakan biopolimer yang terdiri dari monomer asam amino.…”