Villar R, Gil M J, García J I, Martínez-Merino V
Dep. Química Aplicada, Universidad Pública de Navarra, Campus Arrosadía, E-31006 Pamplona, Spain.
J Comput Chem. 2005 Oct;26(13):1347-58. doi: 10.1002/jcc.20276.
We have examined the performance of semiempirical quantum mechanical methods in solving the problem of accurately predicting protein-ligand binding energies and geometries. Firstly, AM1 and PM3 geometries and binding enthalpies between small molecules that simulate typical ligand-protein interactions were compared with high level quantum mechanical techniques that include electronic correlation (e.g., MP2 or B3LYP). Species studied include alkanes, aromatic systems, molecules including groups with hypervalent sulfur or with donor or acceptor hydrogen bonding capability, as well as ammonium or carboxylate ions. B3LYP/6-311+G(2d,p) binding energies correlated very well with the BSSE corrected MP2/6-31G(d) values. AM1 binding enthalpies also showed good correlation with MP2 values, and their systematic deviation is acceptable when enthalpies are used for the comparison of interaction energies between ligands and a target. PM3 otherwise gave erratic energy differences in comparison to the B3LYP or MP2 approaches. As one would expect, the geometries of the binding complexes showed the known limitations of the semiempirical and DFT methods. AM1 calculations were subsequently applied to a test set consisting of "real" protein active site-ligand complexes. Preliminary results indicate that AM1 could be a valuable tool for the design of new drugs using proteins as templates. This approach also has a reasonable computational cost. The ligand-protein X-ray structures were reasonably reproduced by AM1 calculations and the corresponding AM1 binding enthalpies are in agreement with the results from the "small molecules" test set.
我们研究了半经验量子力学方法在准确预测蛋白质 - 配体结合能和几何结构问题上的性能。首先，将模拟典型配体 - 蛋白质相互作用的小分子之间的AM1和PM3几何结构及结合焓与包括电子相关（如MP2或B3LYP）的高水平量子力学技术进行了比较。研究的物种包括烷烃、芳香体系、含有超价硫基团或具有供体或受体氢键能力的基团的分子，以及铵离子或羧酸根离子。B3LYP/6 - 311 + G(2d,p)结合能与经基组重叠误差（BSSE）校正的MP2/6 - 31G(d)值相关性非常好。AM1结合焓与MP2值也显示出良好的相关性，当用焓来比较配体与靶标的相互作用能时，它们的系统偏差是可以接受的。否则，与B3LYP或MP2方法相比，PM3给出的能量差异不稳定。正如人们所预期的，结合复合物的几何结构显示出半经验和密度泛函理论（DFT）方法的已知局限性。随后将AM1计算应用于由“真实”蛋白质活性位点 - 配体复合物组成的测试集。初步结果表明，AM1可能是一种以蛋白质为模板设计新药的有价值工具。这种方法也具有合理的计算成本。AM1计算合理地再现了配体 - 蛋白质X射线结构，相应的AM1结合焓与“小分子”测试集的结果一致。
