Molecular simulations of lipid membrane partitioning and translocation by bacterial quorum sensing modulators

Jin, Tianyi; Patel, Samarthaben J.; Lehn, Reid C. Van

doi:10.1371/journal.pone.0246187

Cited by 16 publications

(29 citation statements)

References 67 publications

(99 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Snapshots from representative distances along the DOPC bilayer normal ( z ) are shown in Figure B. From these free-energy profiles, we defined two free-energy differences, the partition free energy (Δ G par ) and the translocation free energy (Δ G trans ), to compare the likelihood of each compound to intercalate into and translocate across the bilayer, respectively (Figure C) . Δ G par is defined as the difference in free energy between the PMF minimum and the reference state in solution (e.g., z ≥ −4 nm).…”

Section: Resultsmentioning

confidence: 99%

“…Δ G par is defined as the difference in free energy between the PMF minimum and the reference state in solution (e.g., z ≥ −4 nm). Δ G trans is defined as the difference in free energy between the PMF maximum at the bilayer center and the PMF minimum . In these contexts, a more negative value of Δ G par indicates that it is favorable for a compound to partition into the lipid monolayer, and a more positive value of Δ G trans indicates that it is less favorable for a compound to translocate across the lipid bilayer.…”

Section: Resultsmentioning

confidence: 99%

“…From these free-energy profiles, we defined two free-energy differences, the partition free energy (ΔG par ) and the translocation free energy (ΔG trans ), to compare the likelihood of each compound to intercalate into and translocate across the bilayer, respectively (Figure 9C). 74 ΔG par is defined as the difference in free energy between the PMF minimum and the reference state in solution (e.g., z ≥ −4 nm). ΔG trans is defined as the difference in free energy between the PMF maximum at the bilayer center and the PMF minimum.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Bacterial Quorum Sensing Signals Promote Large-Scale Remodeling of Lipid Membranes

et al. 2021

Self Cite

View full text Add to dashboard Cite

We report that N-acyl-L-homoserine lactones (AHLs), a class of nonionic amphiphiles that common bacteria use as signals to coordinate group behaviors, can promote largescale remodeling in model lipid membranes. Characterization of supported lipid bilayers (SLBs) of the phospholipid 1,2-dioleoylsn-glycero-3-phosphocholine (DOPC) by fluorescence microscopy and quartz crystal microbalance with dissipation (QCM-D) reveals the well-studied AHL signal 3-oxo-C12-AHL and its anionic head group hydrolysis product (3-oxo-C12-HS) to promote the formation of long microtubules that can retract into hemispherical caps on the surface of the bilayer. These transformations are dynamic, reversible, and dependent upon the head group structure. Additional experiments demonstrate that 3-oxo-C12-AHL can promote remodeling to form microtubules in lipid vesicles and promote molecular transport across bilayers. Molecular dynamics (MD) simulations predict differences in thermodynamic barriers to translocation of these amphiphiles across a bilayer that are reflected in both the type and extent of reformation and associated dynamics. Our experimental observations can thus be interpreted in terms of accumulation and relief of asymmetric stresses in the inner and outer leaflets of a bilayer upon intercalation and translocation of these amphiphiles. Finally, experiments on Pseudomonas aeruginosa, a pathogen that uses 3-oxo-C12-AHL for cell-tocell signaling, demonstrate that 3-oxo-C12-AHL and 3-oxo-C12-HS can promote membrane remodeling at biologically relevant concentrations and in the absence of other biosurfactants, such as rhamnolipids, that are produced at high population densities. Overall, these results have implications for the roles that 3-oxo-C12-AHL and its hydrolysis product may play in not only mediating intraspecies bacterial communication but also processes such as interspecies signaling and bacterial control of host-cell response. Our findings also provide guidance that could prove useful for the design of synthetic self-assembled materials that respond to bacteria in ways that are useful in the context of sensing, drug delivery, and in other fundamental and applied areas.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Bacterial Quorum Sensing Signals Promote Large-Scale Remodeling of Lipid Membranes

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our findings on chain-length dependence of cellular uptake and bioactivity are consistent with a recent computational study on the energetic barrier for the translocation of lipidated quorum sensing modulators, finding an energetic minimum for the translocation of medium-length lipids. 57 22…”

Section: Discussionmentioning

confidence: 99%

Medium-Length Lipids Facilitate Cell-Permeability and Bioactivity

Capecchi

Hinnah²,

Petit-Jacques

et al. 2021

Preprint

View full text Add to dashboard Cite

The majority of bioactive molecules act on membrane proteins or intracellular targets and therefore needs to partition into or cross biological membranes. Natural products often exhibit lipid modifications to facilitate critical molecule-membrane interactions and in many cases their bioactivity is markedly reduced upon removal of a lipid group. However, despite its importance in nature, lipid-conjugation of small molecules is not commonly used in chemical biology and medicinal chemistry, and the effect of such conjugation has not been systematically studied. To understand the composition of lipids found in natural products, we carried out a chemoinformatic characterization of the ‘natural product lipidome’. According to this analysis, lipidated natural products predominantly contain saturated linear medium-length lipids, which are significantly shorter than those found in membranes and lipidated proteins. To study the usefulness of such modifications in probe design, we systematically explored the effect of lipid conjugation on five different small molecule chemotypes and find that permeability, cellular retention, subcellular localization, and bioactivity can be significantly modulated depending on the type of lipid tail used. We demonstrate that medium-length lipid tails can render impermeable molecules cell-permeable and switch on their bioactivity. Saturated medium-length lipids (e.g. C10) are found to be ideal for the bioactivity of small molecules in mammalian cells, while saturated long-chain lipids (e.g. C18) often significantly reduce bioavailability and activity. Together, our findings suggest that conjugation of small molecules with medium-length lipids could be a powerful strategy for the design of probes and drugs.

show abstract

“…An unrestrained equilibration of the system, using NPT ensemble at 1 bar and 300 K, was performed [ 42 ]. A molecular dynamics simulation production run of 250 ns was conducted using an isothermal isobaric (NPT) ensemble and a Berendsen barostat [ 43 ]. The coordinates were saved at intervals after each stage and the trajectories were analysed.…”

Section: Methodsmentioning

confidence: 99%

Intermolecular Mechanism and Dynamic Investigation of Avian Influenza H7N9 Virus’ Susceptibility to E119V-Substituted Peramivir–Neuraminidase Complex

et al. 2022

View full text Add to dashboard Cite

The H7N9 virus attaches itself to the human cell receptor protein containing the polysaccharide that terminates with sialic acid. The mutation of neuraminidase at residue E119 has been explored experimentally. However, there is no adequate information on the substitution with E119V in peramivir at the intermolecular level. Therefore, a good knowledge of the interatomic interactions is a prerequisite in understanding its transmission mode and subsequent effective inhibitions of the sialic acid receptor cleavage by neuraminidase. Herein, we investigated the mechanism and dynamism on the susceptibility of the E119V mutation on the peramivir–neuraminidase complex relative to the wildtype complex at the intermolecular level. This study aims to investigate the impact of the 119V substitution on the neuraminidase–peramivir complex and unveil the residues responsible for the complex conformations. We employed molecular dynamic (MD) simulations and extensive post-MD analyses in the study. These extensive computational investigations were carried out on the wildtype and the E119V mutant complex of the protein for holistic insights in unveiling the effects of this mutation on the binding affinity and the conformational terrain of peramivir–neuraminidase E119V mutation. The calculated total binding energy (ΔGbind) for the peramivir wildtype is −49.09 ± 0.13 kcal/mol, while the E119V mutant is −58.55 ± 0.15 kcal/mol. The increase in binding energy (9.46 kcal/mol) is consistent with other post-MD analyses results, confirming that E119V substitution confers a higher degree of stability on the protein complex. This study promises to proffer contributory insight and additional knowledge that would enhance future drug designs and help in the fight targeted at controlling the avian influenza H7N9 virus. Therefore, we suggest that experimentalists collaborate with computational chemists for all investigations of this topic, as we have done in our previous studies.

show abstract

Molecular simulations of lipid membrane partitioning and translocation by bacterial quorum sensing modulators

Cited by 16 publications

References 67 publications

Bacterial Quorum Sensing Signals Promote Large-Scale Remodeling of Lipid Membranes

Bacterial Quorum Sensing Signals Promote Large-Scale Remodeling of Lipid Membranes

Medium-Length Lipids Facilitate Cell-Permeability and Bioactivity

Intermolecular Mechanism and Dynamic Investigation of Avian Influenza H7N9 Virus’ Susceptibility to E119V-Substituted Peramivir–Neuraminidase Complex

Contact Info

Product

Resources

About