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Permeation of the three aromatic dipeptides through lipid bilayers: Experimental and computational study
Lee, Brent L. Kuczera, Krzysztof Middaugh, C. Russell Jas, Gouri S.
Lee, Brent L.
Kuczera, Krzysztof
Middaugh, C. Russell
Jas, Gouri S.
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Abstract
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-acetyltryptophanamide (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. Published by AIP Publishing. [http://dx.doi.org/10.1063/1.4954241]
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Publisher's note added August 2016: "This article was originally published online on 27 June 2016 with a sentence missing in the Acknowledgments. After the funding acknowledgments, it should read, “G.S.J. would like to thank Wilson R. Veras Tavarez and Elizabeth De Leon Olmeda of UCC for helpful comments.” AIP Publishing apologizes for this error. All online versions of the article were corrected on 28 June 2016; the article is correct as it appears in the printed version of the journal."
Date
2016-06-27
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AIP Publishing
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Peptides, Lipids, Diffusion, Free energy, Solvents
Citation
Lee, B. L., Kuczera, K., Middaugh, C. R., & Jas, G. S. (2016). Permeation of the three aromatic dipeptides through lipid bilayers: Experimental and computational study. The Journal of Chemical Physics, 144(24). doi:10.1063/1.4954241