Membrane Permeation of a Peptide: It Is Better to be Positive

Cárdenas, Alfredo E.; Shrestha, Rebika; Webb, Lauren J.; Elber, Ron

doi:10.1021/acs.jpcb.5b02122

Cited by 53 publications

(69 citation statements)

References 49 publications

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“…These types of approximations are very useful as the system grows in complexity and size and exact calculations become prohibitively expensive. Milestoning made it possible to investigate kinetics of enzymes [37] and transport through membranes [12] in agreement with experimental observations. These are systems of tens to hundreds of thousands of particles and time scales of milliseconds.…”

Section: Discussionsupporting

confidence: 52%

A Mathematical Framework for Exact Milestoning

Aristoff¹,

Bello-Rivas²,

Elber³

2016

Multiscale Model. Simul.

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Section: Discussionsupporting

confidence: 52%

A Mathematical Framework for Exact Milestoning

Aristoff¹,

Bello-Rivas²,

Elber³

2016

Multiscale Model. Simul.

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“…25 Previous studies of tryptophan using the more advanced method of milestoning report permeation times on the time scale of hours, which are also in agreement with experimental results. 43,44,85,86 Most other studies have also reported much larger and faster permeability coefficients using the inhomogeneous solubilitydiffusion model, which has been discussed in great detail in other works. 18,25,43,44,[87][88][89] Several assumptions underpin the solubility-diffusion model, including memoryless, diffusivetype motion along the reaction coordinate and the presence of only one slow variable describing the motion of the permeant-namely, the translocation along the membrane normal.…”

Section: Permeability Measuresmentioning

confidence: 79%

“…15,89 Many recent studies suggest that an additional rotational barrier exists that slows down the movement of the permeant. 18,43,44,87,89,90 Others hypothesize that membrane and solvent structural fluctuations play an important role as well. 39,85 The CHARMM lipid force field also overestimates the electric field strength within the membrane by a factor of 3, which may be lowering the value of the PMF within the membrane interior and subsequently accelerating the mean passage time.…”

Section: Permeability Measuresmentioning

confidence: 99%

“…14 Recent molecular dynamics studies have focused on a wide variety of molecules passively diffusing through membranes, such as water, [15][16][17] small molecules, [18][19][20][21][22][23] model drug compounds, 6,22,24,25 analgesics, [26][27][28] drug delivery systems, 29,30 dyes, 31,32 other lipids, 33,34 nanoparticles, [35][36][37] toxins, 38 small peptides, 39,40 and even transmembrane proteins. 41,42 However, only a handful of MD studies have examined amino acid-related systems and are confined to tryptophan, [43][44][45] arginine, 46,47 lysine, 47 and amino acid analogues. 48 In terms of potential of mean force (PMF), findings have consistently shown that small nonpolar molecules tend to be preferentially bound in the membrane center, while polar molecules tend to interact favorably with the lipid headgroups and experience a free energy barrier in the center.…”

Section: Introductionmentioning

confidence: 99%

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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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“…Distribution of 17 amino-acid analogs (without main-chain backbone atoms) across a dioleoylphosphatidylcholine (DOPC) bilayer [ 17 ] was obtained by umbrella sampling and revealed the importance of water defects in permeation of polar and charged residues. Other studies focused on the permeation mechanism of specific charged residues such as charged tryptophan [ 18 ] and arginine [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Bias-Exchange Metadynamics Simulation of Membrane Permeation of 20 Amino Acids

Cao

Bian

et al. 2018

IJMS

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Thermodynamics of the permeation of amino acids from water to lipid bilayers is an important first step for understanding the mechanism of cell-permeating peptides and the thermodynamics of membrane protein structure and stability. In this work, we employed bias-exchange metadynamics simulations to simulate the membrane permeation of all 20 amino acids from water to the center of a dipalmitoylphosphatidylcholine (DPPC) membrane (consists of 256 lipids) by using both directional and torsion angles for conformational sampling. The overall accuracy for the free energy profiles obtained is supported by significant correlation coefficients (correlation coefficient at 0.5–0.6) between our results and previous experimental or computational studies. The free energy profiles indicated that (1) polar amino acids have larger free energy barriers than nonpolar amino acids; (2) negatively charged amino acids are the most difficult to enter into the membrane; and (3) conformational transitions for many amino acids during membrane crossing is the key for reduced free energy barriers. These results represent the first set of simulated free energy profiles of membrane crossing for all 20 amino acids.

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Membrane Permeation of a Peptide: It Is Better to be Positive

Cited by 53 publications

References 49 publications

A Mathematical Framework for Exact Milestoning

A Mathematical Framework for Exact Milestoning

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

Bias-Exchange Metadynamics Simulation of Membrane Permeation of 20 Amino Acids

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