Early stages of interactions of cell-penetrating peptide penetratin with a DPPC bilayer

Pourmousa, Mohsen; Karttunen, Mikko

doi:10.1016/j.chemphyslip.2013.02.011

Cited by 18 publications

(23 citation statements)

References 64 publications

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“…The only effect of the bilayer on the structure of the peptide is the disorder of the C-terminus, where the majority of lysines are localized. The structures observed in these simulations are in good agreement with previous computational findings, 13 and with NMR experiments; 7 there is a small difference in terms of the both termini, where some studies find turns instead of coils. Unlike other experimental results 8,24 no β−sheet conformations were found here.…”

Section: A Penetratin Conformations In the Proximity Of The Bilayersupporting

confidence: 81%

“…Within this model, the peptide's conformation is determined by the side chain interactions of its aromatic and basic residues, which prepare it for insertion. Pourmousa et al 13 reported Penetratin's structure as α-helical in the region between residues 2 and 6, and a variety of others, including π-helix and turns, in the rest of the peptide. The authors proposed that the peptide may adopt each structure depending on the initial configuration when it makes the first contact with the bilayer's surface, and that all the different conformations found in the simulation are part of the penetration process, in such a way that, by switching between them, the peptide searches for the optimal shape and orientation that will allow it to penetrate the membrane.…”

Section: Introductionmentioning

confidence: 99%

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Structure and dynamics of Penetratin’s association and translocation to a lipid bilayer

General

Asciutto

2017

AIP Advances

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Penetratin belongs to the important class of small and positively charged peptides, capable of entering cells. The determination of the optimal peptidic structure for translocation is challenging; results obtained so far are varied and dependent on several factors. In this work, we review the dynamics of association of Penetratin with a modeled dioleoyl-phosphatidylcholine (DOPC) lipid membrane using molecular dynamics simulations with last generation force fields. Penetratin’s structural preferences are determined using a Markov state model. It is observed that the peptide retains a helical form in the membrane associated state, just as in water, with the exception of both termini which lose helicity, facilitating the interaction of terminal residues with the phosphate groups on the membrane’s outer layer. The optimal orientation for insertion is found to be with the peptide’s axis forming a small angle with the interface, and with R1 stretching toward the bilayer. The interaction between arginine side-chains and phosphate groups is found to be greater than the corresponding to lysine, mainly due to a higher number of hydrogen bonds between them. The free energy profile of translocation is qualitatively studied using Umbrella Sampling. It is found that there are different paths of penetration, that greatly differ in size of free energy barrier. The lowest path is compatible with residues R10 to K13 leading the way through the membrane and pulling the rest of the peptide. When the other side is reached, the C-terminus overtakes those residues, and finally breaks out of the membrane. The peptide’s secondary structure during this traversal suffers some changes with respect to the association structure but, overall, conserves its helicity, with both termini in a more disordered state.

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Section: A Penetratin Conformations In the Proximity Of The Bilayersupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Structure and dynamics of Penetratin’s association and translocation to a lipid bilayer

General

Asciutto

2017

AIP Advances

View full text Add to dashboard Cite

show abstract

“…This is because we would like to focus on key interactions involving lipid and protein. This approach of not including salt in protein/lipid interaction simulation is well accepted in various studies using either united atom or all-atom force fields (Herce and Garcia, 2007; Dunkin et al, 2011; Hu et al, 2013; Huang and Garcia, 2013; Pourmousa and Karttunen, 2013; Park et al, 2015). …”

Section: Methodsmentioning

confidence: 99%

Maximally asymmetric transbilayer distribution of anionic lipids alters the structure and interaction with lipids of an amyloidogenic protein dimer bound to the membrane surface

Cheng

Chou

Buie

et al. 2016

Chemistry and Physics of Lipids

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We used molecular dynamics simulations to explore the effects of asymmetric transbilayer distribution of anionic phosphatidylserine (PS) lipids on the structure of a protein on the membrane surface and subsequent protein–lipid interactions. Our simulation systems consisted of an amyloidogenic, beta-sheet rich dimeric protein (D42) absorbed to the phosphatidylcholine (PC) leaflet, or protein-contact PC leaflet, of two membrane systems: a single-component PC bilayer and double PC/PS bilayers. The latter comprised of a stable but asymmetric transbilayer distribution of PS in the presence of counterions, with a 1-component PC leaflet coupled to a 1-component PS leaflet in each bilayer. The maximally asymmetric PC/PS bilayer had a non-zero transmembrane potential (TMP) difference and higher lipid order packing, whereas the symmetric PC bilayer had a zero TMP difference and lower lipid order packing under physiologically relevant conditions. Analysis of the adsorbed protein structures revealed weaker protein binding, more folding in the N-terminal domain, more aggregation of the N- and C-terminal domains and larger tilt angle of D42 on the PC leaflet surface of the PC/PS bilayer versus the PC bilayer. Also, analysis of protein-induced membrane structural disruption revealed more localized bilayer thinning in the PC/PS versus PC bilayer. Although the electric field profile in the non-protein-contact PS leaflet of the PC/PS bilayer differed significantly from that in the non-protein-contact PC leaflet of the PC bilayer, no significant difference in the electric field profile in the protein-contact PC leaflet of either bilayer was evident. We speculate that lipid packing has a larger effect on the surface adsorbed protein structure than the electric field for a maximally asymmetric PC/PS bilayer. Our results support the mechanism that the higher lipid packing in a lipid leaflet promotes stronger protein–protein but weaker protein–lipid interactions for a dimeric protein on membrane surfaces.

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“…MD simulation studies on the timescale of tens to hundreds of nanoseconds have successfully helped to model or refine the conformation of AMPs and their aggregation in the presence of membrane-mimicking solvent mixtures, detergent micelles, and lipid bilayers [22][23][24][25][26][27][28][29][30][31][32]. Several studies employed coarsegrained MD (CG-MD) to investigate the behaviour of peptide/ complexes into lipid membrane [33][34][35] (see also an extensive review on CG-MD by Shinoda and collaborators) [36].…”

Section: Introductionmentioning

confidence: 98%

The cooperative behaviour of antimicrobial peptides in model membranes

Wang

Mura

Zhou

et al. 2014

Biochimica et Biophysica Acta (BBA) - Biomembranes

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A systematic analysis of the hypothesis of the antimicrobial peptides' (AMPs) cooperative action is performed by means of full atomistic molecular dynamics simulations accompanied by circular dichroism experiments. Several AMPs from the aurein family (2.5,2.6, 3.1), have a similar sequence in the first ten amino acids, are investigated in different environments including aqueous solution, trifluoroethanol (TFE), palmitoyloleoylphosphatidylethanolamine (POPE), and palmitoyloleoylphosphatidylglycerol (POPG) lipid bilayers. It is found that the cooperative effect is stronger in aqueous solution and weaker in TFE. Moreover, in the presence of membranes, the cooperative effect plays an important role in the peptide/lipid bilayer interaction. The action of AMPs is a competition of the hydrophobic interactions between the side chains of the peptides and the hydrophobic region of lipid molecules, as well as the intra peptide interaction. The aureins 2.5-COOH and 2.6-COOH form a hydrophobic aggregate to minimize the interaction between the hydrophobic group and the water. Once that the peptides reach the water/lipid interface the hydrophobic aggregate becomes smaller and the peptides start to penetrate into the membrane. In contrast, aurein 3.1-COOH forms only a transient aggregate which disintegrates once the peptides reached the membrane, and it shows no cooperativity in membrane penetration.

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Early stages of interactions of cell-penetrating peptide penetratin with a DPPC bilayer

Cited by 18 publications

References 64 publications

Structure and dynamics of Penetratin’s association and translocation to a lipid bilayer

Structure and dynamics of Penetratin’s association and translocation to a lipid bilayer

Maximally asymmetric transbilayer distribution of anionic lipids alters the structure and interaction with lipids of an amyloidogenic protein dimer bound to the membrane surface

The cooperative behaviour of antimicrobial peptides in model membranes

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