Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, United States of America.
PLoS One. 2011;6(9):e24712. doi: 10.1371/journal.pone.0024712. Epub 2011 Sep 22.
There is a great interest in understanding and exploiting protein-protein associations as new routes for treating human disease. However, these associations are difficult to structurally characterize or model although the number of X-ray structures for protein-protein complexes is expanding. One feature of these complexes that has received little attention is the role of water molecules in the interfacial region.
A data set of 4741 water molecules abstracted from 179 high-resolution (≤ 2.30 Å) X-ray crystal structures of protein-protein complexes was analyzed with a suite of modeling tools based on the HINT forcefield and hydrogen-bonding geometry. A metric termed Relevance was used to classify the general roles of the water molecules.
The water molecules were found to be involved in: a) (bridging) interactions with both proteins (21%), b) favorable interactions with only one protein (53%), and c) no interactions with either protein (26%). This trend is shown to be independent of the crystallographic resolution. Interactions with residue backbones are consistent for all classes and account for 21.5% of all interactions. Interactions with polar residues are significantly more common for the first group and interactions with non-polar residues dominate the last group. Waters interacting with both proteins stabilize on average the proteins' interaction (-0.46 kcal mol(-1)), but the overall average contribution of a single water to the protein-protein interaction energy is unfavorable (+0.03 kcal mol(-1)). Analysis of the waters without favorable interactions with either protein suggests that this is a conserved phenomenon: 42% of these waters have SASA ≤ 10 Å(2) and are thus largely buried, and 69% of these are within predominantly hydrophobic environments or "hydrophobic bubbles". Such water molecules may have an important biological purpose in mediating protein-protein interactions.
人们对理解和利用蛋白质-蛋白质相互作用作为治疗人类疾病的新途径非常感兴趣。然而，尽管蛋白质-蛋白质复合物的 X 射线结构数量不断增加，但这些相互作用很难进行结构特征描述或建模。这些复合物的一个特征是界面区域水分子的作用，这一点很少受到关注。
从 179 个高分辨率（≤2.30Å）蛋白质-蛋白质复合物 X 射线晶体结构中提取了 4741 个水分子的数据集，并用基于 HINT 力场和氢键几何形状的一套建模工具进行了分析。使用一个称为相关性的度量标准来对水分子的一般作用进行分类。
发现水分子参与了：a）与两个蛋白质（21%）的（桥接）相互作用，b）仅与一个蛋白质（53%）的有利相互作用，以及 c）与两个蛋白质均无相互作用（26%）。这种趋势与晶体学分辨率无关。与残基骨架的相互作用对于所有类别都是一致的，占所有相互作用的 21.5%。与极性残基的相互作用在第一组中更为常见，而非极性残基的相互作用在最后一组中占主导地位。与两个蛋白质相互作用的水分子平均稳定蛋白质的相互作用（-0.46kcal mol(-1)），但单个水分子对蛋白质-蛋白质相互作用能的总体平均贡献是不利的（+0.03kcal mol(-1)）。对与两个蛋白质均无有利相互作用的水分子进行分析表明，这是一种保守现象：42%的这些水分子的 SASA ≤10Å(2)，因此大部分被埋藏，69%的这些水分子处于主要是疏水性环境或“疏水性气泡”中。这些水分子可能在介导蛋白质-蛋白质相互作用方面具有重要的生物学意义。
