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


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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    • "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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