Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: Successful in silico prediction of the relative permeabilities of cyclic peptides

被引:315
作者
Rezai, Taha
Bock, Jonathan E.
Zhou, Mai V.
Kalyanaraman, Chakrapani
Lokey, R. Scott [1 ]
Jacobson, Matthew P.
机构
[1] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA
[2] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA
关键词
D O I
10.1021/ja063076p
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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.
引用
收藏
页码:14073 / 14080
页数:8
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