Mihalek I, Res I, Lichtarge O
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
J Mol Biol. 2007 Jun 1;369(2):584-95. doi: 10.1016/j.jmb.2007.03.057. Epub 2007 Mar 24.
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.
我们讨论了哪些残基对于蛋白质-蛋白质相互作用足够重要,以至于处于显著的进化压力之下这一问题。其意义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出发,在单个原体上检测蛋白质-蛋白质界面。通过对分子动力学模拟产生的轨迹进行分析,我们认为,对于水溶性蛋白质而言,通过考虑蛋白质界面的动态行为并寻找与大量溶剂交换水分子异常缓慢的残基(暂称为“干性残基”),可以发现很大一部分具有进化优势的残基。我们表明,干性界面残基在同源物中比一般的“几何足迹”更保守,并且通过蛋白质同源物的比较分析能够相当可靠地检测到,而对方法的选择没有强烈依赖。此外,我们表明干性残基通过一组与已知蛋白质寡聚化机制一致的生物物理特性而与众不同:它们的组成向非极性偏移、重叠,以及与低迁移率的残基共定位,它们形成氢键的倾向比几何足迹的其余部分增加两到三倍,参与形成盐桥的可能性增加四到近十倍。这些特性一致地有助于理解观察到的干性残基所经历的进化压力的增加。