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

Department of Chemistry and Biochemistry, University of California at Santa Cruz, Santa Cruz, CA 95064, USA.
Journal of the American Chemical Society (Impact Factor: 12.11). 12/2006; 128(43):14073-80. DOI: 10.1021/ja063076p
Source: PubMed

ABSTRACT 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 R(2) = 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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    • "The Weinstein Lab has already implemented a method that combines both all-atom MD and continuum methods to better understand the energetics of their membrane–protein systems (Mondal et al. 2011). Similarly, the Jacobson Laboratory has created a hybrid approach that uses molecular simulation together with simple solubility-diffusion models through flat membranes to rapidly assess neutral cyclic peptide and small molecule membrane permeability (Rezai et al. 2006a, b; Leung et al. 2012). The incorporation of our membrane bending model into this latter framework may make it possible to explore the permeation of charged and highly polar molecules and peptides, offering opportunities for high-throughput design and screening of novel membrane permeable compounds. "
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    ABSTRACT: Experimental and computational studies have shown that cellular membranes deform to stabilize the inclusion of transmembrane (TM) proteins harboring charge. Recent analysis suggests that membrane bending helps to expose charged and polar residues to the aqueous environment and polar head groups. We previously used elasticity theory to identify membrane distortions that minimize the insertion of charged TM peptides into the membrane. Here, we extend our work by showing that it also provides a novel, computationally efficient method for exploring the energetics of ion and small peptide penetration into membranes. First, we show that the continuum method accurately reproduces energy profiles and membrane shapes generated from molecular simulations of bare ion permeation at a fraction of the computational cost. Next, we demonstrate that the dependence of the ion insertion energy on the membrane thickness arises primarily from the elastic properties of the membrane. Moreover, the continuum model readily provides a free energy decomposition into components not easily determined from molecular dynamics. Finally, we show that the energetics of membrane deformation strongly depend on membrane patch size both for ions and peptides. This dependence is particularly strong for peptides based on simulations of a known amphipathic, membrane binding peptide from the human pathogen Toxoplasma gondii. In total, we address shortcomings and advantages that arise from using a variety of computational methods in distinct biological contexts.
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    • "Bacteria survival percentages were obtained according to ''Materials and methods'' the structure–interaction relationship, as already described by other authors (Rezai et al. 2006a, b; Kwon and Kodadek 2007). This is probably due to the fact that cyclization can increase permeability in the membrane eliminating terminal charges and internally favoring conformations by hydrogen bonds. "
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    ABSTRACT: Cyclic peptides isolated from the plants of the Euphorbiaceae family have been largely studied due to their rigid conformation, which is considered significant for biologic activity. The peptide Labaditin (L(0)) and its open chain analogs (L(1)) were synthesized by the solid-phase peptide synthesis technique (Fmoc/tBu), and purified to elucidate its interaction with membrane models. A shift in λ(max) emission and Stern-Volmer constants values indicate that both tryptophans migrate to a more apolar environment, with L(1) decreasing less than L(0). A circular dichroism (CD) study revealed that L(0) was kept unstructured in aqueous media as much as in the presence of dipalmitoilphosphatidylcholine liposomes. The thermodynamic studies by differential calorimetry (DSC) show a ΔH increase (50 and 18 kcal/mol, for L(0) and L(1), respectively) with peptide concentrations, which is indicative of lipids associating with peptides, resulting in the inability of the lipids to participate in the main transition. Therefore, all CD, DSC, and fluorescence data suggest a greater L(0) membrane insertion. A probable mechanism for Labaditin interaction is based initially on the hydrophobic interaction of the peptide with the lipid membrane, conformational change, peptide adsorption on the lipid surface, and internalization process. Peptide's antibacterial effect was also evaluated and revealed that only L(0) showed reduction in viability in Gram-positive bacteria while no effects to the Gram-negative.
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