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Selectivity and Mechanism of Fengycin, an Antimicrobial Lipopeptide, from Molecular Dynamics.

ABSTRACT: Fengycin is a cyclic lipopeptide used as an agricultural fungicide. It is synthesized by Bacillus subtilis as an immune response against fungal infection and functions by damaging the target's cell membrane. Previous molecular dynamics simulations and experiments have led to the hypothesis that the aggregation of fengycins on the membrane surface plays a key role in cell disruption. Here, we used microsecond-scale all-atom molecular dynamics simulations to understand the specificity, selectivity, and structure of fengycin oligomers. Our simulations suggest that fengycin is more likely to form stable oligomers in model fungal membranes (phosphatidylcholine) compared to the model bacterial membranes (phosphatidylethanolamine:phosphatidylglycerol). Furthermore, we characterize the differences in the structure and kinetics of the membrane-bound aggregates and discuss their functional implications.

SUBMITTER: Sur S

PROVIDER: S-EPMC5832627 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Selectivity and Mechanism of Fengycin, an Antimicrobial Lipopeptide, from Molecular Dynamics.

Sur Sreyoshi S Romo Tod D TD Grossfield Alan A

The journal of physical chemistry. B 20180215 8

Fengycin is a cyclic lipopeptide used as an agricultural fungicide. It is synthesized by Bacillus subtilis as an immune response against fungal infection and functions by damaging the target's cell membrane. Previous molecular dynamics simulations and experiments have led to the hypothesis that the aggregation of fengycins on the membrane surface plays a key role in cell disruption. Here, we used microsecond-scale all-atom molecular dynamics simulations to understand the specificity, selectivity ...[more]

PMID: 29376372

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Project description:TLR7 and TLR8 are key members of the Toll-like receptor family, playing crucial roles in the signaling pathways of innate immunity, and thus become attractive therapeutic targets of many diseases including infections and cancer. Although TLR7 and TLR8 show a high degree of sequence homology, their biological response to small molecule binding is very different. Aiming to understand the mechanism of selective profiles of small molecule modulators against TLR7 and TLR8, we carried out molecular dynamic simulations on three imidazoquinoline derivatives bound to the receptors separately. They are Resiquimod (R), Hybrid-2 (H), and Gardiquimod (G), selective agonists of TLR7 and TLR8. Our MD trajectories indicated that in the complex of TLR7-R and TLR7-G, the two chains forming the TLR7 dimer tended to remain "open" conformation, while the rest systems maintained in the closed format. The agonists R, H, and G developed conformational deviation mainly on the aliphatic tail. Furthermore, we attempted to quantify the selectivity between TLR7 and TLR8 by binding free energies via MM-GBSA method. It showed that the three selected modulators were more favorable for TLR7 than TLR8, and the ranking from the strongest to the weakest was H, R and G, aligning well with experimental data. In the TLR7, the flexible and hydrophobic aliphatic side chain of H has stronger van der Waals interactions with V381 and F351 but only pick up interaction with one amino acid residue i.e. Y353 of TLR8. Unsurprisingly, the positively charged side chain of G has less favorable interaction with I585 of TLR7 and V573 of TLR8 explaining G is weak agonist of both TLR7 and TLR8. All three imidazoquinoline derivatives can form stable hydrogen bonds with D555 of TLR7 and the corresponding D543 of TLR8. In brief, the set of total 400ns MD studies sheds light on the potential selectivity mechanisms of agonists towards TLR7 and TLR8, indicating the van der Waals interaction as the driving force for the agonists binding, thus provides us insights for designing more potent and selective modulators to cooperate with the hydrophobic nature of the binding pocket.

Dataset Information

Selectivity and Mechanism of Fengycin, an Antimicrobial Lipopeptide, from Molecular Dynamics.

Publications

Selectivity and Mechanism of Fengycin, an Antimicrobial Lipopeptide, from Molecular Dynamics.

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