The Structure of a Melittin-Stabilized Pore

Leveritt, John M.; Pino-Ángeles, Almudena; Lazaridis, Themis

doi:10.1016/j.bpj.2015.04.006

Cited by 71 publications

(75 citation statements)

References 26 publications

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“…For melittin, magainin, and PGLa a toroidal pore structure is supported, in which lipid head groups are pulled into the bilayer interior and (some) peptides are stable in the T-state. 51,52 However, for piscidin 1 a pore structure was not stable as the peptides preferred S-state orientations. 53 Transient membrane defects were observed for piscidin 1, which were characterized by the deep insertion of the C-terminal region of the peptide.…”

Section: Discussionmentioning

confidence: 99%

Influence of membrane composition on the binding and folding of a membrane lytic peptide from the non-enveloped flock house virus

Nangia

May

2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Using a combination of coarse-grained and atomistic molecular dynamics simulations we have investigated the membrane binding and folding properties of the membrane lytic peptide of Flock House virus (FHV). FHV is an animal virus and an excellent model system for studying cell entry mechanisms in non-enveloped viruses. FHV undergoes a maturation event where the 44 C-terminal amino acids are cleaved from the major capsid protein, forming the membrane lytic (γ) peptides. Under acidic conditions, γ is released from the capsid interior allowing the peptides to bind and disrupt membranes. The first 21 N-terminal residues of γ, termed γ1, have been resolved in the FHV capsid structure and γ1 has been the subject of in vitro studies. γ1 is structurally dynamic as it adopts helical secondary structure inside the capsid and on membranes, but it is disordered in solution. In vitro studies have shown the binding free energies to POPC or POPG membranes are nearly equivalent, but binding to POPC is enthalpically driven, while POPG binding is entropically driven. Through coarse-grained and multiple microsecond all-atom simulations the membrane binding and folding properties of γ1 are investigated against homogeneous and heterogeneous bilayers to elucidate the dependence of the microenvironment on the structural properties of γ1. Our studies provide a rationale for the thermodynamic data and suggest binding of γ1 to POPG bilayers occurs in a disordered state, but γ1 must adopt a helical conformation when binding POPC bilayers.

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Section: Discussionmentioning

confidence: 99%

Influence of membrane composition on the binding and folding of a membrane lytic peptide from the non-enveloped flock house virus

Nangia

May

2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

View full text Add to dashboard Cite

show abstract

“…4). In contrast to the simulations that were heated to increase sampling, the 15 N chemical shifts were measured at low temperatures to trap the inserted state. Despite these efforts, only S peptides were measurable.…”

Section: Discussionmentioning

confidence: 99%

“…Fig. 4 (top) shows ssNMR spectra for 15 N-labeled V10 p1 in hydrated 3:1 POPC/POPG bilayers aligned on glass plates at a P/L of 1:12 and pH 7.4. At 305 K, well above the phase transition temperature of the lipids (271 K), the TM state was not observed even though the peptide concentration was well above the amount needed to permeabilize the membrane (28,29).…”

Section: Peptide Secondary Structurementioning

confidence: 99%

“…The resulting lipid distortion is evident from 31 P chemical shifts of oriented samples in ssNMR (14). Melittin is the most studied example of a toroidal pore (6,15,16). A subclass, disordered toroidal pores, has been proposed to include pores where peptides with a range of orientations coexist (17), but for the purposes of this study toroidal and disordered toroidal pores are grouped, and distinguished from barrel-stave.…”

Section: Introductionmentioning

confidence: 99%

“…For example, Article I presents a 14-ms trajectory of a six-peptide alamethicin pore in DOPC to demonstrate the stability when using the CHARMM36 lipid and protein parameters (35). Additionally, a four-peptide melittin pore simulated on Anton started in a barrel-stave arrangement quickly became toroidal and remained stable for the duration of the 9-ms trajectory (15). These results, which agree with experimental data, support the notion that a similar simulation protocol can be used to assess the stability of AMP pores.…”

Section: Introductionmentioning

confidence: 99%

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Simulations of Membrane-Disrupting Peptides II: AMP Piscidin 1 Favors Surface Defects over Pores

Perrin

Cotten

et al. 2016

Biophysical Journal

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Antimicrobial peptides (AMPs) that disrupt bacterial membranes are promising therapeutics against the growing number of antibiotic-resistant bacteria. The mechanism of membrane disruption by the AMP piscidin 1 was examined with multimicrosecond all-atom molecular dynamics simulations and solid-state NMR spectroscopy. The primary simulation was initialized with 20 peptides in four barrel-stave pores in a fully hydrated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol bilayer. The four pores relaxed to toroidal by 200 ns, only one porelike structure containing two transmembrane helices remained at 26 ms, and none of the 18 peptides released to the surface reinserted to form pores. The simulation was repeated at 413 K with an applied electric field and all peptides were surface-bound by 200 ns. Trajectories of surface-bound piscidin with and without applied fields at 313 and 413 K and totaling 6 ms show transient distortions of the bilayer/water interface (consistent with 31 P NMR), but no insertion to transmembrane or pore states.15 N chemical shifts confirm a fully surface-bound conformation. Taken together, the simulation and experimental results imply that transient defects rather than stable pores are responsible for membrane disruption by piscidin 1, and likely other AMPs.

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Integrated Design of a Membrane‐Lytic Peptide‐Based Intravenous Nanotherapeutic Suppresses Triple‐Negative Breast Cancer

et al. 2022

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Membrane-lytic peptides offer broad synthetic flexibilities and design potential to the arsenal of anticancer therapeutics, which can be limited by cytotoxicity to noncancerous cells and induction of drug resistance via stress-induced mutagenesis. Despite continued research efforts on membrane-perforating peptides for antimicrobial applications, success in anticancer peptide therapeutics remains elusive given the muted distinction between cancerous and normal cell membranes and the challenge of peptide degradation and neutralization upon intravenous delivery. Using triple-negative breast cancer as a model, the authors report the development of a new class of anticancer peptides. Through function-conserving mutations, the authors achieved cancer cell selective membrane perforation, with leads exhibiting a 200-fold selectivity over non-cancerogenic cells and superior cytotoxicity over doxorubicin against breast cancer tumorspheres. Upon continuous exposure to the anticancer peptides at growth-arresting concentrations, cancer cells do not exhibit resistance phenotype, frequently observed under chemotherapeutic treatment. The authors further demonstrate efficient encapsulation of the anticancer peptides in 20 nm polymeric nanocarriers, which possess high tolerability and lead to effective tumor growth inhibition in a mouse model of MDA-MB-231 triple-negative breast cancer. This work demonstrates a multidisciplinary approach for enabling translationally relevant membrane-lytic peptides in oncology, opening up a vast chemical repertoire to the arms race against cancer.

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The Structure of a Melittin-Stabilized Pore

Cited by 71 publications

References 26 publications

Influence of membrane composition on the binding and folding of a membrane lytic peptide from the non-enveloped flock house virus

Influence of membrane composition on the binding and folding of a membrane lytic peptide from the non-enveloped flock house virus

Simulations of Membrane-Disrupting Peptides II: AMP Piscidin 1 Favors Surface Defects over Pores

Integrated Design of a Membrane‐Lytic Peptide‐Based Intravenous Nanotherapeutic Suppresses Triple‐Negative Breast Cancer

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