On itinerant water molecules and detectability of protein-protein interfaces through comparative analysis of homologues.
On itinerant water molecules and detectability of protein-protein interfaces through comparative analysis of homologues.
复制标题
通过同系物的比较分析研究流动水分子和蛋白质-蛋白质界面的可检测性。
DOI：
10.1016/j.jmb.2007.03.057
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发表时间：
2007
影响因子：
5.6
通讯作者：
Lichtarge,O
中科院分区：
文献类型：
--
作者：
Mihalek,I;Res,I;Lichtarge,O
我们讨论了哪些残基足够重要，使蛋白质相互作用处于显着的进化压力之下的问题。它的兴趣源于这一知识在相反方向的适用性，即从参与残基的突变率开始检测单个原核上的蛋白质-蛋白质界面。利用分子动力学模拟产生的轨迹分析，我们认为，在水溶性蛋白质的情况下，通过考虑蛋白质界面的动态行为和寻找水分子与大部分溶剂交换缓慢的残基(暂定称为“干残基”)，可以找到很大一部分进化特权残基。我们表明，与一般的“几何足迹”相比，干界面残基在同系物中保存得更好，并且可以通过对蛋白质同系物的比较分析来相当可靠地检测到，而不是强烈依赖于方法的选择。此外，我们还表明，干残基通过一系列与已知的蛋白质齐聚机制一致的生物物理性质而脱颖而出：它们的组成向非极性、重叠和与表现出低流动性的残基共存，它们比几何足迹的其余部分增加两到三倍形成氢键的倾向，参与盐桥形成的可能性增加四到几乎十倍。这些特性有助于理解观察到的干残留物所经历的进化压力的增加。
We discuss the question of which residues are sufficiently important for protein–protein interaction to be under notable evolutionary pressure. Its interest stems from the applicability of this knowledge in the reverse direction, to detect a protein–protein interface on a single protomer, starting from the rate of mutation of participating residues. Using the analysis of trajectories produced by the molecular dynamics simulations, we suggest that, in the case of water soluble proteins, a large fraction of evolutionarily privileged residues can be found by considering the dynamic behavior of the protein interface and by looking for residues which exchange water molecules with the bulk of the solvent outstandingly slowly (tentatively termed “dry residues”). We show that the dry interface residues are better conserved across homologues than the generic “geometric footprint” and can be quite reliably detected through comparative analysis of protein homologues, without strong dependence on the choice of method. Furthermore, we show that dry residues distinguish themselves through a set of biophysical properties consistent with the known mechanisms of protein oligomerization: their compositional shift toward nonpolar, overlap, and co-location with residues exhibiting low mobility, their two- to threefold increased propensity over the rest of the geometric footprint to form hydrogen bonds, and four- to almost tenfold increased likelihood to participate in formation of salt bridges. These properties, consistently, help understand the observed increase in the evolutionary pressure that dry residues experience.