Molecular dynamics simulations of conformational behavior of linear RGD peptidomimetics and cyclic prodrugs in aqueous and octane solutions.
Molecular dynamics simulations of conformational behavior of linear RGD peptidomimetics and cyclic prodrugs in aqueous and octane solutions.
复制标题
线性 RGD 拟肽和环状前药在水溶液和辛烷溶液中构象行为的分子动力学模拟。
DOI：
10.1080/07391102.2002.10506784
复制
发表时间：
2002
影响因子：
4.4
通讯作者：
Kuczera,Krysztof
中科院分区：
文献类型：
--
作者：
Mahadevan,Janaki;Xu,Christine;Siahaan,Teruna;Kuczera,Krysztof
用CHARMM程序进行了1 ns长的分子动力学模拟，探索了一类环状前体药物和相应的线性RGD多肽的构象。采用显式模拟的水和辛烷作为溶剂，模拟了溶质在跨细胞转运过程中从水分配到膜时所经历的环境变化。在水中，线性多肽类药物倾向于聚集在延伸型结构中，具有与溶剂强烈的有利相互作用和低的固有稳定性的特点。在这些延长的构象中，带电的末端能够承担很大的距离，对于最长的系统来说，超过15？这些线性多肽类药物在实验研究中被发现显示出最高的效力，这与实验观察到的RGD多肽的趋势一致。相反，在辛烷中，线型多肽的致密构象更受青睐，所有带电基团聚集在一起，不受溶剂的影响，表现出高的本征稳定性和弱的溶质-溶剂相互作用。我们的计算预测了将线性体系从水转移到辛烷的大量不利的能量变化，这与实验结果一致，即这些化合物不是通过跨细胞途径转移的。环状前体药物在水和辛烷中的模拟没有显示出主要的结构差异，在两种溶剂中都采用了转折构象。环状结构对环境变化的反应有限，导致能量从水转移到辛烷，这也是不利的，但比线性分子小得多。这一效应与观察到的环状前体药物的被动跨细胞转运增强是一致的。
Conformations available to a class of cyclic prodrugs and corresponding linear RGD peptidomimetics were explored using 1 ns length molecular dynamics simulations performed with the program CHARMM. Water and octane, modeled explicitly, were used as solvents to mimic the change of the environment experienced by the solutes upon partition from water to membrane in the trans-cellular transport process. In water, the linear peptidomimetics tended to populate extended-like structures, characterized by strong favorable interactions with solvent and low intrinsic stability. In these extended conformations the charged termini are able to assume large distances, above 15 Å for the longest systems. These linear peptidomimetics have been found to exhibit the highest potency in experimental studies, in accord with the trends experimentally observed for RGD peptides. In contrast, in octane compact conformers of the linear peptidomimetics were favored, with all charged groups aggregated and shielded from solvent, exhibiting high intrinsic stability and weak solute-solvent interactions. Our calculations predict a large unfavorable energy change for transferring the linear systems from water to octane, in agreement with experimental findings that these compounds are not transported via the trans-cellular pathway. The cyclic pro- drugs did not exhibit major structural differences between the simulations in water and octane, adopting turn-like conformations in both solvents. The limited response of the cyclic structures to changes in the environment leads to energies of transfer from water to octane that are also unfavorable, but much less so than for the linear molecules. This effect is in accord with the observed enhanced passive trans-cellular transport of the cyclic prodrugs.