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Conformational Flexibility, Internal Hydrogen Bonding, and Passive Membrane Permeability:  Successful in Silico Prediction of the Relative Permeabilities of Cyclic Peptides

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    Conformational Flexibility, Internal Hydrogen Bonding, and Passive Membrane Permeability:  Successful in Silico Prediction of the Relative Permeabilities of Cyclic Peptides
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    Contribution from the Department of Chemistry and Biochemistry, University of California at Santa Cruz, Santa Cruz, California 95064, and Department of Pharmaceutical Chemistry, University of California at San Francisco, 600 16th Street, San Francisco, California 94143-2240
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    Cite this: J. Am. Chem. Soc. 2006, 128, 43, 14073–14080
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    https://doi.org/10.1021/ja063076p
    Published October 6, 2006
    Copyright © 2006 American Chemical Society
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    Abstract

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    We report an atomistic physical model for the passive membrane permeability of cyclic peptides. The computational modeling was performed in advance of the experiments and did not involve the use of “training data”. The model explicitly treats the conformational flexibility of the peptides by extensive conformational sampling in low (membrane) and high (water) dielectric environments. The passive membrane permeabilities of 11 cyclic peptides were obtained experimentally using a parallel artificial membrane permeability assay (PAMPA) and showed a linear correlation with the computational results with R2 = 0.96. In general, the results support the hypothesis, already well established in the literature, that the ability to form internal hydrogen bonds is critical for passive membrane permeability and can be the distinguishing factor among closely related compounds, such as those studied here. However, we have found that the number of internal hydrogen bonds that can form in the membrane and the solvent-exposed polar surface area correlate more poorly with PAMPA permeability than our model, which quantitatively estimates the solvation free energy losses upon moving from high-dielectric water to the low-dielectric interior of a membrane.

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     University of California at Santa Cruz.

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     University of California at San Francisco.

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    In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

    Supporting Information Available

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    Detailed experimental procedures on compound synthesis and PAMPA, computationally predicted low-dielectric structures for all cyclic peptides tested experimentally, and detailed computational data for the virtual cyclic peptide library. This material is available free of charge via the Internet at http://pubs.acs.org.

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    This article is cited by 336 publications.

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    Cite this: J. Am. Chem. Soc. 2006, 128, 43, 14073–14080
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