How To Tackle the Issues in Free Energy Simulations of Long Amphiphiles Interacting with Lipid Membranes: Convergence and Local Membrane Deformations

Filipe, Hugo A. L.; Moreno, Maria João; Róg, Tomasz; Vattulainen, Ilpo; Loura, Luís M. S.

doi:10.1021/jp501622d

Cited by 68 publications

(107 citation statements)

References 57 publications

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“…This effect has been found in previous studies, and has been attributed primarily to the presence of more than one slow variable characterizing membrane permeation, among which peptide orientation and large-scale membrane structural fluctuations have been proposed. 25,27,30,96 The accommodation of additional slow variables is an exciting topic of current inquiry.…”

Section: Discussionmentioning

confidence: 99%

Permeation of the three aromatic dipeptides through lipid bilayers: Experimental and computational study

Lee

Kuczera

Middaugh

et al. 2016

The Journal of Chemical Physics

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The time-resolved parallel artificial membrane permeability assay with fluorescence detection and comprehensive computer simulations are used to study the passive permeation of three aromatic dipeptides—N-acetyl-phenylalanineamide (NAFA), N-acetyltyrosineamide (NAYA), and N-acetyl-tryptophanamide (NATA) through a 1,2-dioleoyl-sn-glycero-3-phospocholine (DOPC) lipid bilayer. Measured permeation times and permeability coefficients show fastest translocation for NAFA, slowest for NAYA, and intermediate for NATA under physiological temperature and pH. Computationally, we perform umbrella sampling simulations to model the structure, dynamics, and interactions of the peptides as a function of z, the distance from lipid bilayer. The calculated profiles of the potential of mean force show two strong effects—preferential binding of each of the three peptides to the lipid interface and large free energy barriers in the membrane center. We use several approaches to calculate the position-dependent translational diffusion coefficients D(z), including one based on numerical solution the Smoluchowski equation. Surprisingly, computed D(z) values change very little with reaction coordinate and are also quite similar for the three peptides studied. In contrast, calculated values of sidechain rotational correlation times τrot(z) show extremely large changes with peptide membrane insertion—values become 100 times larger in the headgroup region and 10 times larger at interface and in membrane center, relative to solution. The peptides’ conformational freedom becomes systematically more restricted as they enter the membrane, sampling α and β and C7eq basins in solution, α and C7eq at the interface, and C7eq only in the center. Residual waters of solvation remain around the peptides even in the membrane center. Overall, our study provides an improved microscopic understanding of passive peptide permeation through membranes, especially on the sensitivity of rotational diffusion to position relative to the bilayer.

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Section: Discussionmentioning

confidence: 99%

Permeation of the three aromatic dipeptides through lipid bilayers: Experimental and computational study

Lee

Kuczera

Middaugh

et al. 2016

The Journal of Chemical Physics

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“…This probe in particular displays perfect matching with POPC acyl chains, and its packing and ordering abilities may be related to the reported favourable partition into liquid ordered phases of NBD-diC 16 PE and NBD-diC 18 PE (the latter should be better accommodated inside domains enriched in longer, predominantly saturated chains such as those of sphingomyelin inside lipid rafts). However, full clarification of this matter will involve additional work, focused on cholesterol-containing liquid ordered bilayers, and including calculation of the changes in solute free energy across the bilayer (as recently done by us for the NBD-C n series in POPC 89 ).…”

Section: Discussionmentioning

confidence: 99%

Behaviour of NBD-head group labelled phosphatidylethanolamines in POPC bilayers: a molecular dynamics study

Filipe

Santos

Ramalho

et al. 2015

Phys. Chem. Chem. Phys.

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A complete homologous series of fluorescent phosphatidylethanolamines (diC n PE), labelled at the head group with a 7-nitrobenz-2-oxa-1,3-diazo-4-yl(NBD) fluorophore and inserted in 1-palmitoyl, 2-oleoyl-snglycero-3-phosphocholine (POPC) bilayers, was studied using atomistic molecular dynamics simulations. The longer-chained derivatives of NBD-diC n PE, with n = 14, 16, and 18, are commercially available, and widely used as fluorescent membrane probes. Properties such as location of atomic groups and acyl chain order parameters of both POPC and NBD-diC n PE, fluorophore orientation and hydrogen bonding, membrane electrostatic potential and lateral diffusion were calculated for all derivatives in the series. Most of these probes induce local disordering of POPC acyl chains, which is on the whole counterbalanced by ordering resulting from binding of sodium ions to lipid carbonyl/glycerol oxygen atoms. An exception is found for NBD-diC 16 PE, which displays optimal matching with POPC acyl chain length and induces a slight local ordering of phospholipid acyl chains. Compared to previously studied fatty amines, acyl chain-labelled phosphatidylcholines, and sterols bearing the same fluorescent tag, the chromophore in NBD-diC n PE locates in a similar region of the membrane (near the glycerol backbone/carbonyl region) but adopts a different orientation (with the NO 2 group facing the interior of the bilayer). This modification leads to an inverted orientation of the P-N axis in the labelled lipid, which affects the interface properties, such as the membrane electrostatic potential and hydrogen bonding to lipid head group atoms. The implications of this study for the interpretation of the photophysical properties of NBD-diC n PE (complex fluorescence emission kinetics, differences with other NBD lipid probes) are discussed.

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“…30 for discussion about translocation of long amphiphilic chains moving through a membrane, a system with many similarities to ours). Specifically, in our study we found that the lipid bilayer was too easily deformed while pushing the peptide inside of it, in some cases to the point of reaching the boundary of the simulation box, such that it could affect the assumptions of periodic boundary conditions (PBC) (one imagines a smooth transition from one periodic cell to the other, not transitions where the membrane forms sharp angles).…”

Section: B Umbrella Samplingmentioning

confidence: 93%

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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How To Tackle the Issues in Free Energy Simulations of Long Amphiphiles Interacting with Lipid Membranes: Convergence and Local Membrane Deformations

Cited by 68 publications

References 57 publications

Permeation of the three aromatic dipeptides through lipid bilayers: Experimental and computational study

Permeation of the three aromatic dipeptides through lipid bilayers: Experimental and computational study

Behaviour of NBD-head group labelled phosphatidylethanolamines in POPC bilayers: a molecular dynamics study

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

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