Thermodynamic stability of β-peptide helices and the role of cyclic residues
Thermodynamic stability of β-peptide helices and the role of cyclic residues
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DOI：
10.1529/biophysj.106.084491
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发表时间：
2006-11-01
影响因子：
3.4
通讯作者：
de Pablo, Juan J.
中科院分区：
文献类型：
--
作者：
Rathore, Nitin;Gellman, Samuel H.;de Pablo, Juan J.
β-肽作为一类有吸引力的肽模拟物分子而出现。与天然存在的α-肽相反，β-氨基酸的短寡聚体（仅包含4-6个单体）表现出稳定的二级结构，这使得它们适合于特定化学相互作用对结构的影响的定量、协调的实验和理论研究。在这项工作中，分子模拟被用来研究的热力学稳定性的螺旋构象所形成的β-肽含有不同比例的非环状（β（3））和环状（ACH）残基。更具体地说，在这项工作中考虑了几种β-肽，其不同之处仅在于它们的环状残基含量。以前的β-肽的计算研究主要依赖于分子动力学模拟的能量最小化。相比之下，我们的研究依赖于基于状态密度的Monte Carlo模拟来计算自由能，并检查这些分子的各种折叠结构的稳定性沿着一个定义良好的序参数。通过诉诸扩展系综形式主义，我们能够确定展开特定分子所需的自由能，这个量可以通过单分子力谱直接测量。在隐式和显式溶剂中的模拟已经允许环状残基和静电对二级结构的稳定性的作用的系统研究。在这项工作中考虑的分子显示出稳定的H-14螺旋构象，在某些情况下，相对稳定的H-12构象，从而表明溶剂质量可用于操纵这些肽的氢键模式和结构。
Beta-peptides are emerging as an attractive class of peptidomimetic molecules. In contrast to naturally occurring alpha-peptides, short oligomers of beta-amino acids (comprising just 4-6 monomers) exhibit stable secondary structures that make them amenable for quantitative, concerted experimental and theoretical studies of the effects of particular chemical interactions on structure. In this work, molecular simulations are used to study the thermodynamic stability of helical conformations formed by beta-peptides containing varying proportions of acyclic (beta(3)) and cyclic (ACH) residues. More specifically, several beta-peptides differing only in their content of cyclic residues are considered in this work. Previous computational studies of beta-peptides have relied mostly on energy minimization of molecular dynamics simulations. In contrast, our study relies on density-of-states based Monte Carlo simulations to calculate the free energy and examine the stability of various folded structures of these molecules along a well-defined order parameter. By resorting to an expanded-ensemble formalism, we are able to determine the free energy required to unfold specific molecules, a quantity that could be measured directly through single-molecule force spectroscopy. Simulations in both implicit and explicit solvents have permitted a systematic study of the role of cyclic residues and electrostatics on the stability of secondary structures. The molecules considered in this work are shown to exhibit stable H-14 helical conformations and, in some cases, relatively stable H-12 conformations, thereby suggesting that solvent quality may be used to manipulate the hydrogen-bonding patterns and structure of these peptides.