Functional group contributions to peptide permeability in lipid bilayer membranes : the role of peptide conformation and length

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Title Functional group contributions to peptide permeability in lipid bilayer membranes : the role of peptide conformation and length
Publication Type dissertation
School or College College of Pharmacy
Department Pharmaceutics & Pharmaceutical Chemistry
Author Mayer, Peter T.
Contributor Schackmann, Bob
Date 2001-12
Description Successful prediction of drug transport rates across biological membranes and partitioning in the body based on structure alone requires an understanding of the factors controlling passive diffusion across lipid bilayer membranes as this is the major route of entry. The barrier domain solubility-diffusion model predicts that passive diffusion of small polar molecules across egg lecithin bilayers is controlled by partitioning from water into the ordered acyl chain region. The lipid bilayer permeability coefficient (P) can be predicted from the organic solvent/water partition coefficient (PC) provided that an appropriate bulk organic solvent having the same physicochemical properties as the barrier domain is chosen. The appropriate bulk solvent is one that gives a slope of 1.0 in a plot of log(P) versus log(PC). Apparent substituent contributions to the free energy of transfer from water into the barrier domain (?(?G°) P = -RTln(P RX /P RH )) were determined by comparing permeability coefficients of substituted compounds (P RX ) to reference (P RH ) compounds using large unilamellar vesicles (LUVs) composed of egg lecithin. Independence of group contributions was verified by evaluating the effect of substitution at the ?-methyl position of both p -toluic and p -methylhippuric acid. These studies demonstrated that 1,9-decadiene precisely mimics the barrier domain. As the permeants were increased in size the functional group independence was lost as the residue (?(?G°) P values decreased as size increased. Residue contributions varied considerably: glycine, 2510-4490 cal/mol, (3460 average); alanine, 2800-3680 cal/mol (3240 average); sarcosine, 1250-3990 cal/mol (2270 average); N-methylation (-2220 to -288 cal/mol, (-1300 average)). The variability suggest that predictions of membrane permeability using whole residue contributions may be unreliable without considering intramolecular hydrogen-bonding and the various conformations which may exist within membranes. Molecular dynamics simulations were performed in water and 1,9-decadiene. These simulations provided evidence for more prevalent intramolecular hydrogen bonding interactions in 1,9-decadiene. A strong correlation of log(P) with log(PC 1,9-decadiene ) was observed even for peptides that fold in 1,9-decadiene. This suggests that the non-additivities exhibited in functional group contributions generated from permeability coefficients are also evident in bulk solvent/water partitioning. This supports the hypothesis that intramolecular hydrogen-bonding is a primary factor contributing to nonindependence.
Type Text
Publisher University of Utah
Subject Functional Group; Permeability; Lipid Bilayer Membranes Peptide Conformation; Pharmacology; Pharmacokinetics; Lipid Membranes: Bilayer Lipid Membranes: Peptides
Subject MESH DNA; ATP-Binding Cassette Transporters; Chromatin
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Functional group contributions to peptide permeability in lipid bilayer membranes : the role of peptide conformation and length." Spencer S. Eccles Health Sciences Library. Print version of "Functional group contributions to peptide permeability in lipid bilayer membranes : the role of peptide conformation and length." available at J. Willard Marriott Library Special Collection. RM31.5 2001 .M39.
Rights Management © Peter T. Mayer.
Format application/pdf
Format Medium application/pdf
Format Extent 3,791,624 bytes
Identifier undthes,5380
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Funding/Fellowship NIH grant RO1 Gm51347, a Higuchi Fellowship Award, and NIH Cross-Training Fellowship Award and Pharmaceutical Research and Manufactures of American Foundation (PhRMA) Advanced Predoctoral Fellowhsip.
Master File Extent 3,791,674 bytes
ARK ark:/87278/s6xk8hdc
Setname ir_etd
ID 191544
Reference URL https://collections.lib.utah.edu/ark:/87278/s6xk8hdc
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