Charge-Based Interactions between Peptides Observed as the Dominant Force for Association in Aqueous Solution
Charge-Based Interactions between Peptides Observed as the Dominant Force for Association in Aqueous Solution
复制标题
DOI：
10.1002/anie.200802679
复制
发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Watts, Anthony
中科院分区：
文献类型：
--
作者：
McLain, Sylvia E.;Soper, Alan K.;Watts, Anthony
尽管进行了大量的研究，但蛋白质在溶液中折叠成其生物功能形式的过程仍然没有得到很好的理解。蛋白质中疏水性氨基酸侧链的缔合-疏水效应-经常被认为是蛋白质在体内折叠的基本驱动力。[1-4]然而，几乎没有直接的实验证据支持这一论断，并且纯粹从疏水缔合的蛋白质组装给出了折叠过程的不完整画面。虽然许多完全折叠的蛋白质核心含有相关的疏水残基，但离子对或盐桥在稳定蛋白质结构方面很重要，并且一部分蛋白质的核心中埋有离子对。[5]此外，疏水核的存在不一定暗示疏水力是折叠的主要驱动力。为了进一步了解疏水和亲水相互作用在蛋白质形成过程中的相对作用，我们通过使用中子衍射和计算机模拟技术相结合，确定了三个二肽片段在水溶液中的结构，所述二肽片段包含暴露于周围水溶剂的疏水和亲水部分。研究的一系列肽由甘氨酰-L-丙氨酸、甘氨酰-L-脯氨酸和L-丙氨酰-L-脯氨酸组成（图1）。这些二肽的疏水性在整个系列中增加;甘氨酸具有最小的疏水基团（-H），丙氨酸具有单个甲基（-CH 3），脯氨酸具有最大的疏水基团及其吡咯烷环（-CH（N）（CH 2）3）。[6]选择脯氨酸进行这项研究，因为它是疏水性和可溶性的，足以使中子衍射实验可行。请注意，甘氨酰-L-丙氨酸中的肽键是仲酰胺，而其他两个二肽是叔酰胺（图1）。氢同位素取代增强的中子衍射（NDHIS）结合计算机模拟提供了关于溶液中分子排列的原子长度尺度信息。[7-11]通过应用NDHIS结合经验势结构细化（EPSR;见实验部分）建模，可以提取与衍射实验一致的溶液的三维结构。
The process by which proteins fold in solution into their biologically functional forms is still not well understood despite intense research. The association of hydrophobic amino acid side chains in proteins—the hydrophobic effect—is frequently invoked to be the fundamental driving force behind protein folding in vivo.[1–4] However, there is little direct experimental evidence that supports this assertion, and protein assembly purely from hydrophobic association gives an incomplete picture of the folding process. While many fully folded protein cores contain associated hydrophobic residues, ion pairs or salt bridges are important in stabilizing protein structures, and a proportion of proteins have ion pairs buried in their core.[5] Moreover, the presence of a hydrophobic core does not necessarily implicate hydrophobic forces as the primary driving force of folding. To gain further understanding of the relative roles of hydrophobic and hydrophilic interactions in the process of protein formation, we determined the structure in aqueous solution of three dipeptide fragments containing both hydrophobic and hydrophilic portions exposed to the surrounding water solvent by using a combination of neutron diffraction and computer simulation techniques. The series of peptides investigated consisted of glycyl-L-alanine, glycyl-L-proline, and L-alanyl-L-proline (Figure1). The hydrophobicity of these dipeptides increases across the series; glycine has the smallest hydrophobic group (-H), alanine a single methyl group (-CH3), and proline has the largest hydrophobic group with its pyrrolidine ring (-CH (N)(CH2) 3).[6] Proline was chosen for this investigation as it is both hydrophobic and soluble enough to make the neutron diffraction experiments feasible. Note that the peptide bond in glycyl-L-alanine is a secondary amide, whereas the other two dipeptides are tertiary amides (Figure 1).Neutron diffraction enhanced by hydrogen isotope substitution (NDHIS) when combined with computer simulation provides atomic-length-scale information about the arrangement of molecules in solution.[7–11] Through the application of NDHIS coupled with modeling by empirical potential structure refinement (EPSR; see the Experimental Section), it is possible to extract three-dimensional structures of the solution which are consistent with the diffraction experi-