Very fast prediction and rationalization of pKa values for protein-ligand complexes
Very fast prediction and rationalization of pKa values for protein-ligand complexes
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DOI：
10.1002/prot.22102
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发表时间：
2008-11-15
影响因子：
2.9
通讯作者：
Jensen, Jan H.
中科院分区：
文献类型：
--
作者：
Bas, Delphine C.;Rogers, David M.;Jensen, Jan H.
将预测蛋白质中可电离残基pK（a）值的PROPKA方法扩展到包括非蛋白质配体对蛋白质pK（a）值的影响以及预测配体本身上可电离基团pK（a）值的变化。这个新版本的PROPKA（PROPKA 2.0），尽可能多地，通过调整PROPKA 1.0的经验规则，配体官能团。因此，PROPKA的速度得以保持，因此对于大多数蛋白质，所有可电离基团的pK（a）值都可以在几秒钟内计算出来。通过比较PROPKA 2.0预测26蛋白质-配体复合物的实验数据，包括胰蛋白酶，凝血酶，三种胃蛋白酶，HIV-1蛋白酶，胰凝乳蛋白酶，木聚糖酶，羟基腈裂解酶，和二氢叶酸还原酶，这种适应是有效的。对于胰蛋白酶和凝血酶，在实验中观察到14种配体复合物中有4种的质子化状态发生了较大变化（竖线n> 0.5）。PROPKA 2.0和Klebe的PEOE方法（Czodrowski P等人，J Mol Biol 2007;367：1347-1356）都鉴定了四个大的质子化状态变化中的三个。质子化状态的变化，由于血浆蛋白酶11，组织蛋白酶D和endothiapepsin结合到胃蛋白酶抑制剂预测在0.4质子单位内，在pH 6.5和7.0，分别。PROPKA 2.0的结果表明，由于配体结合的结构变化，有助于显着的质子吸收/释放，作为远离结合位点的残基，主要是由于在一个特定的残基的局部环境的变化，因此在局部氢键网络的变化。总的来说，结果表明PROPKA 2.0提供了对可滴定基团的pK（a）值具有重要影响的蛋白质-配体相互作用的良好描述，从而允许快速准确地确定关键残基和配体功能的质子化状态。
The PROPKA method for the prediction of the pK(a) values of ionizable residues in proteins is extended to include the effect of non-proteinaceous ligands on protein pK(a) values as well as predict the change in pK(a) values of ionizable groups on the ligand itself. This new version of PROPKA (PROPKA 2.0) is, as much as possible, developed by adapting the empirical rules underlying PROPKA 1.0 to ligand functional groups. Thus, the speed of PROPKA is retained, so that the pK(a) values of all ionizable groups are computed in a matter of seconds for most proteins. This adaptation is validated by comparing PROPKA 2.0 predictions to experimental data for 26 protein-ligand complexes including trypsin, thrombin, three pepsins, HIV-1 protease, chymotrypsin, xylanase, hydroxynitrile lyase, and dibydrofolate reductase. For trypsin and thrombin, large protonation state changes (vertical bar n vertical bar > 0.5) have been observed experimentally for 4 out of 14 ligand complexes. PROPKA 2.0 and Klebe's PEOE approach (Czodrowski P, et al. J Mol Biol 2007;367:1347-1356) both identify three of the four large protonation state changes. The protonation state changes due to plasmepsin 11, cathepsin D and endothiapepsin binding to pepstatin are predicted to within 0.4 proton units at pH 6.5 and 7.0, respectively. The PROPKA 2.0 results indicate that structural changes due to ligand binding contribute significantly to the proton uptake/release, as do residues far away from the binding site, primarily due to the change in the local environment of a particular residue and hence the change in the local hydrogen bonding network. Overall the results suggest that PROPKA 2.0 provides a good description of the protein-ligand interactions that have an important effect on the pK(a) values of titratable groups, thereby permitting fast and accurate determination of the protonation states of key residues and ligand functional