Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 3. The free energy contribution of structural water molecules in HIV-1 protease complexes
Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 3. The free energy contribution of structural water molecules in HIV-1 protease complexes
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DOI：
10.1021/jm030596b
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发表时间：
2004-08-26
影响因子：
7.3
通讯作者：
Kellogg, GE
中科院分区：
文献类型：
--
作者：
Fornabaio, M;Spyrakis, F;Kellogg, GE
蛋白质活性中心内的结构水分子与配体-蛋白质识别有关，因为它们改变了活性中心的几何形状，并有助于结合亲和力。在这项工作中，分析了23个配体与二聚体HIV-1蛋白酶的相互作用。这些配合物的X-射线结构表明存在四种结构水分子：水301(对称轴上)、水313、水313bis和外围水。除了水301，这些通常与对称相关的集合相辅相成。网格程序既用于检查水的位置，也用于放置由于结晶学不确定性而似乎从络合物中缺失的水分子。使用HINT对能量贡献进行的水化学分析表明，当考虑适当的桥联水分子时，HINT分数与实验确定的结合常数之间的相关性得到显著改善。在无水的情况下，r(2)=0.30，标准误差为+/-1.30千卡摩尔(-1)；当考虑约束水的能量贡献时，r(2)=0.61，标准误差为0.98千卡摩尔(-1)。HINT被证明能够定量地映射单个结构水对结合能的贡献。与各种类型的水相关的顺序是水301；水313；水313；水313；周边水域。因此，为了获得最可靠的自由能预测，结构水分子的贡献应该包括在内。然而，必须注意包括增加信息价值的水分子的影响，而不仅仅是噪音。
Structural water molecules within protein active sites are relevant for ligand-protein recognition because they modify the active site geometry and contribute to binding affinity. In this work an analysis of the interactions between 23 ligands and dimeric HIV-1 protease is reported. The X-ray structures of these complexes show the presence of four types of structural water molecules: water 301 (on the symmetry axis), water 313, water 313bis, and peripheral waters. Except for water 301, these are generally complemented with a symmetry-related set. The GRID program was used both for checking water locations and for placing water molecules that appear to be missing from the complexes due to crystallographic uncertainty. Hydropathic analysis of the energetic contributions using HINT indicates a significant improvement of the correlation between HINT scores and the experimentally determined binding constants when the appropriate bridging water molecules are taken into account. In the absence of water r(2) = 0.30 with a standard error of +/- 1.30 kcal mol(-1) and when the energetic contributions of the constrained waters are included r(2) = 0.61 with a standard error of 0,98 kcal mol(-1). HINT was shown to be able to map quantitatively the contribution of individual structural waters to binding energy. The order of relevance for the various types of water is water 301 > water 313 > water 313bis > peripheral waters. Thus, to obtain the most reliable free energy predictions, the contributions of structural water molecules should be included. However, care must be taken to include the effects of water molecules that add information value and not just noise.