Xiang Tian-Xiang, Anderson Bradley D
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
J Pharm Sci. 2006 Jun;95(6):1269-87. doi: 10.1002/jps.20453.
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.
肽跨脂质双层转运的限速屏障是其非极性烃内部。渗透肽在从水溶液转移到屏障区域的过程中可能会发生构象变化，从而促进肽的转运。为了验证这一假设，我们对一系列先前用于转运实验的小肽对甲苯基 - Ala(n)（n = 0 - 3）进行了全原子和显式溶剂分子动力学（MD）模拟，以探索它们在水和四氯化碳（CCl₄）中的构象结构、动力学和溶剂化自由能。研究发现，对甲苯基丙氨酸二肽和三肽在水中的构象远非无规卷曲，以Ⅱ型螺旋（P(II)）和α-螺旋（α(R)）为主，但七元环（c(7)）和五元环（c(5)）的比例较小。相比之下，在四氯化碳中，七元环c(7)与c(5)占主导。这些结果表明，丙氨酸肽的构象偏好对溶剂高度敏感。动力学上，稳定的七元环形成发生在10皮秒的时间尺度上，而更大的环尺寸（如十元环）则很少观察到。相邻扭转角（φ₁，ψ₁）的值取决于相邻扭转角。相邻扭转的热运动导致c(7)、c(5)、α(R)和P(II)构象之间的转变具有高度协同性，而相邻扭转组（φ₁，ψ₁）和（φ₂，ψ₂）转变之间的长程相关性则不太明显。肽在四氯化碳中的折叠降低了分子内静电能。这与疏水相互作用一起，有利于肽分配到四氯化碳中。这些效应仅部分抵消了在水中更有利的其他类型的分子内相互作用和肽 - 溶剂极性相互作用，导致不利于肽从水转移到四氯化碳的净转移自由能（3 - 7千卡/摩尔）。
