Sequence-dependent interaction of β-peptides with membranes.
Sequence-dependent interaction of β-peptides with membranes.
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β-肽与膜的序列依赖性相互作用。
DOI：
10.1021/jp1070242
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
A. Yethiraj
中科院分区：
文献类型：
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作者：
Jagannath Mondal;Xiao Zhu;Q. Cui;A. Yethiraj
最近的实验研究揭示了β-肽抗菌活性的有趣序列依赖性，这表明合理设计新的抗菌剂的可能性。为了深入了解膜活性的机制，我们提出了一个计算机模拟研究这些分子的吸附到一个单组分脂质膜。研究了两类分子：14-螺旋序列的10-残基低聚物和4个无规共聚β-肽序列。感兴趣的寡聚物是10-残基、14-螺旋序列的全局两亲性（GA）和非全局两亲性（非GA）序列。在溶液中和界面处，所有低聚物在整个模拟过程中保持螺旋结构。分子进入膜的渗透和分子在界面处的取向强烈地依赖于序列。我们将此归因于β-苯丙氨酸（βF）残基渗透膜的倾向。对于四种无规共聚β-肽序列，隐式溶剂和膜模型的模拟表明，聚合物的吸附强度与其分离疏水性和阳离子残基的效率密切相关。模拟结果为抗菌β-肽候选物的设计提供了简单的策略。总的来说，这些结果进一步支持了最近几项研究的结论，即短肽有效地与膜相互作用既不需要全局两亲性，也不需要规则的二级结构。此外，虽然我们只研究了结合过程，但在计算的结合特性和实验观察到的抗微生物活性中的序列依赖性之间存在相关性的事实表明，与膜的有效结合可能是高抗微生物活性的良好预测因子。
Recent experimental studies have revealed interesting sequence dependence in the antimicrobial activity of β-peptides, which suggests the possibility of a rational design of new antimicrobial agents. To obtain insight into the mechanism of membrane activity, we present a computer simulation study of the adsorption of these molecules to a single-component lipid membrane. Two classes of molecules are investigated: 10-residue oligomers of 14-helical sequences, and four sequences of random copolymeric β-peptides. The oligomers of interest are globally amphiphilic (GA) and nonglobally amphiphilic (non-GA) sequences of 10-residue, 14-helical sequences. In solution and at the interface, all oligomers maintain a helical structure throughout the simulation. The penetration of the molecules into the membrane and the orientation of the molecules at the interface depend strongly on the sequence. We attribute this to the propensity of the β-phenylalanine (βF) residues for membrane penetration. For the four sequences of random copolymeric β-peptides, simulations of an implicit solvent and membrane model show that the strength of adsorption of the polymers is strongly correlated with their efficiency to segregate the hydrophobic and cationic residues. The simulations suggest simple strategies for the design of candidates for antimicrobial β-peptides. Collectively, these results further support the conclusion from several recent studies that neither global amphiphilicity nor regular secondary structure is required for short peptides to effectively interact with the membrane. Moreover, although we study only the binding process, the fact that there is a correlation between the sequence dependence in the calculated binding properties and the experimentally observed antimicrobial activity suggests that efficient binding to the membrane might be a good predictor for high antimicrobial activity.