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Bradley D Anderson

Publications and source records attributed to Bradley D Anderson.

At least 19 recordsLinked to original sources
PubMed2006

Liposomal drug transport: a molecular perspective from molecular dynamics simulations in lipid bilayers.

Computational methods to predict drug permeability across biomembranes prior to synthesis are increasingly desirable to minimize the investment in drug design and development. Significant progress in molecular dynamics (MD) simulation methodologies applied to lipid bilayer membranes, for example, is making it possible to move beyond characterization of the membranes themselves to explore various thermodynamic and kinetic processes governing membrane binding and transport. Such methods are also likely to be directly applicable to the design and optimization of liposomal delivery systems. MD simulations are particularly valuable in addressing issues that are difficult to explore in laboratory experiments due to the heterogeneity of lipid bilayer membranes at the molecular level. Insights emerging from MD simulations are contributing to an understanding of which regions within bilayers are most and least favored by solutes at equilibrium as the solute structure is varied, local diffusivities of permeants, and the origin of the amplified selectivity to permeant size imposed by lipid bilayer membranes, particularly as changes in composition increase acyl chain ordering.

Biological Transport↗
PubMed2006

Kinetics and mechanism for the reaction of cysteine with hydrogen peroxide in amorphous polyvinylpyrrolidone lyophiles.

PURPOSE: Peroxide impurities play a critical role in drug oxidation. In metal-free aqueous solutions, hydrogen peroxide (H(2)O(2)) induced thiol oxidation involves a bimolecular nucleophilic reaction to form a reactive sulfenic acid intermediate (RSOH), which reacts with a second thiol to form a disulfide (RSSR). This study examines the reaction of cysteine (CSH) and H(2)O(2) in amorphous polyvinylpyrrolidone (PVP) lyophiles to explore the possible relevance of the solution mechanism to reactivity in an amorphous glass. MATERIALS AND METHODS: Amorphous PVP lyophiles containing CSH and H(2)O(2) at varying initial 'pH' and reactant concentrations were prepared by methods designed to minimize reaction during lyophilization. Kinetic studies were conducted anaerobically at 25 degrees C and reactants and products were monitored by HPLC. Products were characterized and the kinetic data were fit to models adapted from the solution mechanism. RESULTS: Key differences in the reactions in aqueous solution and amorphous PVP are: (1) while only cystine (CSSC) forms in solution, three degradants-cysteine sulfinic acid (CSO(2)H), cysteine sulfonic acid (CSO(3)H) and cystine (CSSC)--form in amorphous PVP; (2) simple bimolecular kinetics govern the solution reaction while initial rates in amorphous PVP suggested more complex kinetics (i.e., non-unity values for reaction order); and (3) heterogeneous (i.e., biphasic) reaction dynamics are evident in amorphous PVP. The differences in product formation and apparent reaction orders in the solid-state could be rationalized by partitioning of the same reactive intermediate to multiple products in the solid-state due to the restricted mobility of CSH. Beyond the initial rate region, the kinetics in amorphous PVP could be described by the Kohlrausch-Williams-Watts (KWW) stretched-exponential equation or by assuming two populations of reactant molecules having different reactivities. CONCLUSIONS: When reactive intermediates are involved, differences in degradant profiles and other characteristics (e.g., rate constants, apparent reaction order) in the amorphous-state may simply reflect altered rates for individual reaction steps due to glass-induced changes in relative reactant mobilities rather than a change in overall mechanism.

Algorithms↗
PubMed2006

Validation of an HPLC method for analysis of DB-67 and its water soluble prodrug in mouse plasma.

A method for the quantitation of DB-67 ((20S)-10-hydroxy-7-tert-butyldimethylsilylcamptothecin) lactone and carboxylate in mouse plasma has been developed, validated, and applied in pharmacokinetic studies. The analytes were separated by reversed-phase chromatography with fluorescence detection. Validation demonstrated the selectivity and specificity for the carboxylate and lactone, with linearity between 1-300ng/mL and 2.5-300ng/mL for the carboxylate and lactone, respectively (accuracy 90-110% of theory and coefficient of variation < or =5.7%). Carboxylate to lactone conversion was <4% using this method. The assay was found to be suitable for the analysis of DB-67 lactone and carboxylate in pharmacokinetic studies following intravenous administration of DB-67 or its delta-aminobutyric acid ester derivative.

Animals↗
PubMed2006

Kinetics and mechanisms of activation of alpha-amino acid ester prodrugs of camptothecins.

The alpha-amino acid ester prodrugs of the antitumor agent camptothecin and a more potent, lipophilic silatecan analogue, DB-67, have been shown by NMR spectroscopy and quantitative kinetic analyses to undergo quantitative conversion to their pharmacologically active lactones via a nonenzymatic mechanism that at pH 7.4 is favored over direct hydrolysis. The alternate pathway involves the reversible intramolecular nucleophilic amine attack at the camptothecin E-ring carbonyl to generate a lactam (I) followed by a second intramolecular reaction to produce a bicyclic hemiortho ester (I'). The intermediates were isolated and shown to exist in an apparent equilibrium dominated by the hemiortho ester in DMSO using NMR spectroscopy. The conversion of prodrugs of camptothecin or DB-67 containing either alpha-NH(2) or alpha-NHCH(3) and their corresponding hemiortho esters were monitored versus time in aqueous buffer (pH 3.0 and 7.4) at 37 degrees C, and the kinetic data were fit to a model based on the proposed mechanism. The results indicated that while the prodrugs are relatively stable at pH 3, facile lactone release occurs from both the prodrugs and their corresponding hemiortho ester intermediates under physiological conditions (pH 7.4). The glycinate esters and their hemiortho esters were found to be more cytotoxic than the N-methylglycinates or their corresponding hemiortho ester intermediates in vitro using a human breast cancer cell line (MDA-MB-435S), consistent with their more rapid conversion to active lactone. The pH dependence of the nonenzymatic pathway for conversion of these alpha-amino acid ester prodrugs suggests that they may be useful for tumor-targeting via liposomes, as they can be stabilized in an acidic environment in the core of liposomes and readily convert to the active lactone following their intratumoral release.

Amino Acids↗
PubMed2006

Synthesis and biological assays of E-ring analogs of camptothecin and homocamptothecin.

Analogs of the anti-tumor agent camptothecin with both closed E-rings (lactone and ether) and open E-rings (reduced acid, hydrazide, and protected Weinreb amide) have been prepared and tested in topoisomerase and cellular assays. The results provide insights into the structural features of the camptothecin E-ring that affect biological activity.

Antineoplastic Agents↗
PubMed2006

CGHScan: finding variable regions using high-density microarray comparative genomic hybridization data.

BACKGROUND: Comparative genomic hybridization can rapidly identify chromosomal regions that vary between organisms and tissues. This technique has been applied to detecting differences between normal and cancerous tissues in eukaryotes as well as genomic variability in microbial strains and species. The density of oligonucleotide probes available on current microarray platforms is particularly well-suited for comparisons of organisms with smaller genomes like bacteria and yeast where an entire genome can be assayed on a single microarray with high resolution. Available methods for analyzing these experiments typically confine analyses to data from pre-defined annotated genome features, such as entire genes. Many of these methods are ill suited for datasets with the number of measurements typical of high-density microarrays. RESULTS: We present an algorithm for analyzing microarray hybridization data to aid identification of regions that vary between an unsequenced genome and a sequenced reference genome. The program, CGHScan, uses an iterative random walk approach integrating multi-layered significance testing to detect these regions from comparative genomic hybridization data. The algorithm tolerates a high level of noise in measurements of individual probe intensities and is relatively insensitive to the choice of method for normalizing probe intensity values and identifying probes that differ between samples. When applied to comparative genomic hybridization data from a published experiment, CGHScan identified eight of nine known deletions in a Brucella ovis strain as compared to Brucella melitensis. The same result was obtained using two different normalization methods and two different scores to classify data for individual probes as representing conserved or variable genomic regions. The undetected region is a small (58 base pair) deletion that is below the resolution of CGHScan given the array design employed in the study. CONCLUSION: CGHScan is an effective tool for analyzing comparative genomic hybridization data from high-density microarrays. The algorithm is capable of accurately identifying known variable regions and is tolerant of high noise and varying methods of data preprocessing. Statistical analysis is used to define each variable region providing a robust and reliable method for rapid identification of genomic differences independent of annotated gene boundaries.

Algorithms↗
PubMed2006

Dependence of nelfinavir brain uptake on dose and tissue concentrations of the selective P-glycoprotein inhibitor zosuquidar in rats.

Most reverse transcriptase and protease inhibitors used in highly active antiretroviral therapy for treating human immunodeficiency virus (HIV) infections exhibit poor penetration into the brain, raising the concern that the brain may be a sanctuary site for the development of resistant HIV variants. This study explores the relationship between the dose and plasma and brain concentrations of zosuquidar and the effect of this selective P-glycoprotein inhibitor on central nervous system penetration of the HIV protease inhibitor nelfinavir maintained at steady state by intravenous infusions in rats. Nelfinavir was infused (10 mg/kg/h) for up to 10 h with or without concurrent administration of an intravenous bolus dose of 2, 6, or 20 mg/kg zosuquidar given at 4 h. Brain tissue and plasma were analyzed for both drug concentrations. Brain tissue/plasma nelfinavir concentration ratios (uncorrected for the vascular contribution) increased nonlinearly with zosuquidar dose from 0.06 +/- 0.03 in the absence of zosuquidar and 0.09 +/- 0.02 between 2 and 6 h after 2 mg/kg zosuquidar to 0.85 +/- 0.19 after 6 mg/kg and 1.58 +/- 0.67 after 20 mg/kg zosuquidar. Zosuquidar brain tissue/plasma concentration ratios exhibited a similar abrupt increase from 2.8 +/- 0.3 after a 2 mg/kg dose to approximately 15 after the 6 and 20 mg/kg doses. The apparent threshold in the plasma concentration of zosuquidar necessary to produce significant enhancement in brain uptake of nelfinavir appears to be close to the plasma concentrations associated with the maximum tolerated dose reported in the literature after repeated dosing of zosuquidar in patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

ASAP: a resource for annotating, curating, comparing, and disseminating genomic data.

ASAP is a comprehensive web-based system for community genome annotation and analysis. ASAP is being used for a large-scale effort to augment and curate annotations for genomes of enterobacterial pathogens and for additional genome sequences. New tools, such as the genome alignment program Mauve, have been incorporated into ASAP in order to improve display and analysis of related genomes. Recent improvements to the database and challenges for future development of the system are discussed. ASAP is available on the web at https://asap.ahabs.wisc.edu/asap/logon.php.

Databases, Nucleic Acid↗
PubMed2006

Conformational structure, dynamics, and solvation energies of small alanine peptides in water and carbon tetrachloride.

The rate-limiting barrier for peptide transport across lipid bilayers is the nonpolar hydrocarbon interior. Permeating peptides may undergo conformational changes during their transfer from an aqueous solution into the barrier domain, thus facilitating peptide transport. To test this hypothesis, all-atom and explicit-solvent molecular dynamics (MD) simulations have been conducted on a series of small peptides, p-toluyl-Ala(n) (n = 0-3) used previously in transport experiments, to explore their conformational structures, dynamics and solvation free energies in water and carbon tetrachloride (CCl(4)). The conformations of the p-toluyl alanine di- and tri-peptides in water were found to be far from random coils, with P(II) and alpha(R) dominating but with smaller populations of seven-membered (c(7)) and five-membered rings (c(5)). In contrast, the seven-membered ring, c(7), along with c(5) dominated in CCl(4). These results indicate that the conformational preferences of the alanine peptides are highly sensitive to solvent. Dynamically, stable seven-membered ring formation occurred on a time scale of 10 ps while larger ring-sizes (e.g., 10-membered rings) were observed much less frequently. The values of adjacent torsional angles (phi(1), psi(1)) were dependent on neighboring torsional angles. Thermal motions of neighboring torsions leading to transitions between c(7), c(5), alpha(R), and P(II) conformers were highly cooperative while longer range correlations between transitions of adjacent sets of torsions (phi(1), psi(1)) and (phi(2), psi(2)) were less evident. Peptide folding in CCl(4) lowers the intramolecular electrostatic energies. This, along with hydrophobic interactions, favors partitioning into CCl(4). These effects only partially offset other types of intramolecular interactions and peptide-solvent polar interactions that are more favorable in water, leading to net transfer free energies (3-7 kcal/mol) that disfavor peptide transfer from water into carbon tetrachloride.

Alanine↗
PubMed2005

Distribution and effect of water content on molecular mobility in poly(vinylpyrrolidone) glasses: a molecular dynamics simulation.

PURPOSE: This work explores the distribution of water and its effects on molecular mobilities in poly(vinylpyrrolidone) (PVP) glasses using molecular dynamics (MD) simulation technology. METHODS: PVP glasses containing 0.5% and 10% w/w water and a small amount of ammonia and Phe-Asn-Gly were generated. Physical aging processes and associated structural and dynamic properties were monitored vs. time for periods up to 0.1 micros by MD simulation. RESULTS: Increasing water content from 0.5% to 10% w/w was found to reduce the Tg by about 90 K and increase the rates of volume and enthalpy relaxation. At 0.5% w/w, water molecules are mostly isolated and uniformly distributed while at 10% w/w, water distribution is markedly heterogeneous, with strands of water molecules occupying channels between the polymer chains. At 10% w/w, each water molecule has an average of 2.0 neighboring water molecules. The plasticization effects of water were revealed in diffusion coefficient increases of 3.7-, 7.3-, and 7.6-fold for water, ammonia, and the individual polyvinylpyrrolidone segments, respectively, and in shorter relaxation times (37- to 47-fold) for rotation of polymer segments with an elevation in water content from 0.5% to 10% w/w. Water diffusivity was found to linearly correlate with the number of neighboring water molecules. Rotation of the PVP segments is comprised of a fast wobble motion within a highly restrained cavity and a slow rotation over a wider angular space. Only the slow rotation was shown to be significantly affected by water content. CONCLUSIONS: Water distribution in the PVP glass is highly heterogeneous at 10% w/w water, reflecting the formation of water strands or small clusters rather than complete phase separation. Local enhancement of mobility with increasing water content has been demonstrated using MD simulations.

Algorithms↗
PubMed2005

Kinetics and mechanism of the reaction of cysteine and hydrogen peroxide in aqueous solution.

The oxidation of thiol-containing small molecules, peptides, and proteins in the presence of peroxides is of increasing biological and pharmaceutical interest. Although such reactions have been widely studied there does not appear to be a consensus in the literature as to the reaction products formed under various conditions, the reaction stoichiometry, and the reaction mechanisms that may be involved. This study examines the reaction kinetics of cysteine (CSH) with hydrogen peroxide (H(2)O(2)) in aqueous buffers (in the absence of metal ions) over a wide range of pH (pH 4-13) and at varying ratios of initial reactant concentrations to explore the range of conditions in which a two-step nucleophilic model describes the kinetics. The disappearance of CSH and H(2)O(2) and appearance of cystine (CSSC) versus time were monitored by reverse-phase high-performance liquid chromatography (HPLC). The effects of oxygen, metal ions (Cu(2+)), pH (4-13), ionic strength, buffer concentration, and temperature were evaluated. Data obtained at [H(2)O(2)](0)/[CSH](0) ratios from 0.01-2.3 demonstrate that the reaction of CSH with H(2)O(2) in the absence of metal ions is quantitatively consistent with a two-step nucleophilic reaction mechanism involving rate-determining nucleophilic attack of thiolate anion on the unionized H(2)O(2) to generate cysteine sulfenic acid (CSOH) as an intermediate. Second-order rate constants for both reaction steps were generated through model fitting. At [H(2)O(2)](0)/[CSH](0) > 10, the % CSSC formed as a product of the reaction declines due to the increased importance of alternative competing pathways for consumption of CSOH. A thorough understanding of the mechanism in aqueous solution will provide valuable background information for current studies aimed at elucidating the influence of such factors on thiol oxidation in solid-state formulations.

Buffers↗
PubMed2005

Role of P-glycoprotein in distribution of nelfinavir across the blood-mammary tissue barrier and blood-brain barrier.

As a first approach in understanding the possible efficacy and toxicity of human immunodeficiency virus protease inhibitors during breast feeding, the milk-to-plasma ratio of nelfinavir was determined in lactating rats. The milk-to-plasma ratio of nelfinavir was determined to be 0.56 +/- 0.10 (means +/- standard deviations). Western blotting indicated that P-glycoprotein is expressed in rat mammary and brain tissue; however, the multidrug-resistant modulator GF120918 showed a significant effect only at the blood-brain barrier and not at the mammary-epithelial tissue barrier.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

HIV in central nervous system and behavioral development: an HIV-2287 macaque model of AIDS.

OBJECTIVE: To determine which route of inoculation produced consistent and frequent HIV infection in the central nervous system (CNS) and alterations in cognitive and motor development in infant macaques. METHODS: Infant macaques (Macaca nemestrina) were inoculated with the highly pathogenic strain HIV-2287 intravenously (n = 3) or intrathecally (n = 3). Uninfected infants were evaluated as controls. Disease progression was evaluated by virological assessment of blood and cerebral spinal fluid (CSF), CD4 T cell count in blood, and quinolinic acid levels in CSF (a surrogate marker of neuronal cell damage). The effect of HIV infection on cognitive and motor development in infants was monitored during the 6-month study. RESULTS: Either route of HIV-2287 inoculation produced detectable viral RNA in CSF and productive infection in blood. Detection of virus in CSF paralleled a rise in quinolinic acid levels. All HIV-infected infants experienced a severe and rapid decline in CD4 T cell counts by 10 weeks after viral infection. HIV-infected infants, particularly those infected by the intravenous route, exhibited delays in reaching cognitive and motor milestones, which paralleled neuropathological changes. CONCLUSIONS: The HIV-2287 infant model produced a high incidence of viral infection in the CNS regardless of the route of inoculation. Significant alteration in neurobehavioral development was observed in HIV-infected infants, and this measure was significantly impaired particularly in infants infected by the intravenous route. These data, coupled with the ability to detect viral RNA and changes in quinolinic acid levels in CSF, may allow quantitative evaluation of drug and immune candidates for treating neurological effects of AIDS.

AIDS Dementia Complex↗
PubMed2004

A molecular dynamics simulation of reactant mobility in an amorphous formulation of a peptide in poly(vinylpyrrolidone).

The reaction pathways available for chemical decomposition in amorphous solids are determined in part by the relative mobilities of the potential reactants. In this study, molecular dynamics simulations of amorphous glasses of polyvinylpyrrolidone (PVP) containing small amounts of water, ammonia, and a small peptide, Phe-Asn-Gly, have been performed over periods of up to 100 ns to monitor the aging processes and associated structural and dynamic properties of the PVP segments and embedded solutes. Glass transition temperatures, Tg, were detected by changes in slopes of the volume-temperature profiles and the internal energy-temperature profiles for the inherent structures upon cooling at different rates. Analyses of the molecular trajectories below Tg reveal both temporal and spatial heterogeneity in polymer and solute mobility, with each molecule or part of a molecule displaying quite different relaxation behaviors for translational, rotational, and/or conformational motions. Rotations of individual polymer segments on the time scale up to 100 ns, though far from complete, are described by the Kohlrausch-Williams-Watts stretched exponential function with relaxation times tau on the order of 10-2.8 x 10(4) micros at an averaged stretching parameter beta of 0.39. The rotation rates are, on the average, faster for the side chains and for segments near the ends of the chains than for the backbones and segments near the middle of the chains. In contrast to their behavior in water, solute diffusive motions in the glassy polymer exhibit non-Einsteinian behavior over the time scale of the simulations characterized by two types of motion: (1) entrapments within relatively fluid microdomains surrounded by a matrix of relatively immobile polymer chains; and (2) jumps between microdomains with greater probability of hopping back to the solute's previous location. The average jump length and frequency are highly dependent on solute size, being much smaller for the tripeptide, Phe-Asn-Gly, than for water and ammonia. The diffusivities of water and ammonia, solutes capable of forming hydrogen bonds with the lactam residues within the polymer segments, are significantly reduced by strong electrostatic interactions. The conformational preferences of Phe-Asn-Gly were compared in the amorphous polymer and water to detect differences in the degree to which the tripeptide may be predisposed toward deamidation of the asparagine side chain in these environments. Although only minor differences are evident in peptide conformation, the conformational dynamics for the peptide embedded in the glassy polymer are characterized by a higher energy barrier between conformational states and 2.5-44-fold larger relaxation times for the dihedral angles of interest than in water. However, in the context of peptide deamidation, these differences may be of secondary importance in comparison to the more than two to three orders of magnitude reduction in the diffusivities of water, ammonia, and the tripeptide in PVP.

Algorithms↗
PubMed2004

Predictive relationships for the effects of triglyceride ester concentration and water uptake on solubility and partitioning of small molecules into lipid vehicles.

The ability to predict drug solubility and partitioning in triglyceride solvents from the chemical structures of the solute and the triglyceride would be highly useful in drug formulation development and in screening drug candidates for lipid solubility and possibly drug bioavailability. This study explores the role of triglyceride ester concentration on small molecule partitioning between lipid vehicles and water, including the effect of ester concentration on water uptake. The influence of solvated water is further examined in studies of small molecule solubility in dry and water saturated lipid vehicles varying in triglyceride ester concentration. A series of model solutes with varying hydrogen bond donating/accepting abilities was chosen for this study while triglyceride ester concentrations were varied by using squalane/tricaprylin solvent mixtures. General linear free energy solvation relationships having the form utilized previously by Abraham were obtained at each solvent composition. An examination of the solvent descriptors indicated that those descriptors representing the sensitivity of the solvent to the solute dipolarity/polarizability, s, and to the hydrogen bond acidity of the solute, a, vary systematically with the concentration of ester moieties in the solvent mixture. An empirical equation has been derived that offers the potential for predicting triglyceride/water partition coefficients and in certain cases, solubility in hydrated, fully-saturated triglyceride solvents for any small molecule for which Abraham solute descriptors can be obtained. Water uptake in triglyceride vehicles is shown to be approximately linear with water activity and may also be described by the empirical relationship developed for other solutes providing an adjustment is made in the value of its hydrogen bond acidity parameter. Water uptake enhances the solubility of benzamide and N-methylbenzamide and a modest "water-dragging" effect by N-methylbenzamide in the triglycerides is observed.

Dose-Response Relationship, Drug↗
PubMed2004

Determination of carrier-mediated transport of 2',3'-dideoxypurine nucleosides in the rat ileum using a bidirectional perfusion technique.

PURPOSE: Previous attempts to ascertain the role of uptake and efflux transporters in the oral absorption of anti-HIV dideoxypurine nucleosides have been inconclusive. A novel in situ intestinal perfusion technique with complete mesenteric arterial/venous cannulation was used to examine the asymmetry of ileal dideoxynucleoside permeability under near in vivo conditions. METHODS: Intestinal perfusions were performed in the rat ileum, with cannulation of the artery and vein immediately entering and leaving the segment. Urea and mannitol were used as passive permeability markers, and the directional transport of 2',3'-dideoxyinosine (ddI), 2'-beta-fluoro-2',3'-dideoxyinosine (F-ddI), and 2'-beta-fluoro-2',3'-dideoxyadenosine (F-ddA) were examined. RESULTS: Urea and mannitol exhibited symmetric permeability (PLtoB = PBtoL), whereas F-ddI and ddI showed significantly higher permeability in blood-to-lumen transport (PBtoL > PLtoB). PBtoL for F-ddA exceeded PLtoB, but the difference did not reach significance at p < 0.05. PBtoL for ddI was demonstrated to be saturable with increasing ddI concentrations, but PLtoB was independent of ddI concentration. PBtoL for ddI was shown to be dependent on sodium concentration and inhibited by probenecid. CONCLUSIONS: Symmetric transport was demonstrated for urea and mannitol as expected for these passive permeability markers. F-ddI and ddI were shown to be preferentially transported from blood to lumen. The basolateral to luminal transport of ddI is saturable, inhibited by probenecid, and sodium ion dependent. These results are consistent with carrier-mediated uptake on the basolateral membrane.

Animals↗
PubMed2003

A hydrophobicity scale for the lipid bilayer barrier domain from peptide permeabilities: nonadditivities in residue contributions.

Passive peptide transport across lipid membranes is governed by the energetics of partitioning into the ordered chain interior coupled with the rate of diffusion across this region. A hydrophobicity scale for peptide transfer into the barrier region of membranes derived from permeability coefficients would be useful to predict passive permeation of peptides across biomembranes and for determining the thermodynamics of peptide/protein insertion into the membrane interior. This study reports transport rates across large unilamellar vesicles (LUVs) composed of egg lecithin at 25 degrees C for a series of peptides having the general structure N-p-toluyl-(X)(n) (n =1-3), where X is glycine, alanine, or sarcosine. Apparent residue group contributions were calculated from permeability coefficients, P(RX), using the equation Delta(Delta G degrees )(X) = -RT ln(P(RX)/P(RH)). Multiple linear least-squares regression analysis performed for the set of 14 permeants yielded the best correlation (r(2) = 0.9993) when the following permeant descriptors were utilized: side-chain nonpolar surface area, number of -CONH- residues, number of toluyl-CON(Me)- residues, and number of other -CON(Me)- residues. The backbone -CONH- residue contribution in peptides, 4.6 kcal/mol, is significantly lower than that obtained for a single isolated -CONH- (>6 kcal/mol), suggesting a possible influence of intramolecular hydrogen bonding. Under closer scrutiny, Delta(Delta G degrees )(X) for the Ala and Gly residues decrease with increasing peptide length. The effect of N-methylation is also highly dependent on position and number of N-methyl groups on the molecule (Delta(Delta G degrees )(X) = -0.5 to -2.2 kcal/mol). These nonadditivities may be rationalized by considering the effects of peptide length and N-methylation on membrane-induced intramolecular hydrogen bonding leading to various folded conformations.

Alanine↗