Ivanov Ivaylo, Vemparala Satyavani, Pophristic Vojislava, Kuroda Kenichi, DeGrado William F, McCammon J Andrew, Klein Michael L
Department of Chemistry and Biochemistry, University of California-San Diego, La Jolla, CA 92093, USA.
J Am Chem Soc. 2006 Feb 15;128(6):1778-9. doi: 10.1021/ja0564665.
We have applied molecular dynamics to investigate the structural properties and activity of recently synthesized amphiphilic polymethacrylate derivatives, designed to mimic the antimicrobial activity of natural peptides. The composition, molecular weight, and hydrophobicity (ratio of hydrophobic and cationic units) of these short copolymers can be modulated to achieve structural diversity, which is crucial in controlling the antimicrobial activity. We have carried out all-atom molecular dynamics to systematically investigate the conformations adopted by these copolymers in water and at the water-lipid interface as a function of sequence and the chemical nature of the monomers. For two sequences, we observe partial insertion into the bilayer. Formation of strong interactions between the lipid headgroups and the amine groups of the polymers assists in the initial association with the lipids. However, the primary driving force for the observed partial insertion appears to be the hydrophobic effect. Our results indicate sensitive dependence of the overall shape on the sequence, suggesting that experimentally observed changes in activity can be correlated with particular sequences, providing an avenue for rational design.
我们应用分子动力学来研究最近合成的两亲性聚甲基丙烯酸酯衍生物的结构性质和活性，这些衍生物旨在模拟天然肽的抗菌活性。这些短共聚物的组成、分子量和疏水性（疏水单元与阳离子单元的比例）可以进行调节，以实现结构多样性，这对于控制抗菌活性至关重要。我们进行了全原子分子动力学研究，以系统地研究这些共聚物在水中以及在水 - 脂质界面所采取的构象，作为序列和单体化学性质的函数。对于两个序列，我们观察到它们部分插入到双层中。脂质头部基团与聚合物的胺基之间形成的强相互作用有助于聚合物与脂质的初始缔合。然而，观察到的部分插入的主要驱动力似乎是疏水效应。我们的结果表明整体形状对序列敏感依赖，这表明实验观察到的活性变化可以与特定序列相关联，为合理设计提供了一条途径。
