Cheng Y H, Cheng X L, Radić Z, McCammon J A
Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0365, USA.
Chem Biol Interact. 2008 Sep 25;175(1-3):196-9. doi: 10.1016/j.cbi.2008.04.044. Epub 2008 May 7.
The reaction mechanisms of two inhibitor TFK(+) and TFK(0) binding to H447I mutant mouse acetylcholinesterase (mAChE) have been investigated by using a combined ab initio quantum mechanical/molecular mechanical (QM/MM) approach and classical molecular dynamics (MD) simulations. TFK(+) binding to the H447I mutant may proceed with a different reaction mechanism from the wild-type. A water molecule takes over the role of His447 and participates in the bond breaking and forming as a "charge relayer". Unlike in the wild-type mAChE case, Glu334, a conserved residue from the catalytic triad, acts as a catalytic base in the reaction. The calculated energy barrier for this reaction is about 8kcal/mol. These predictions await experimental verification. In the case of the neutral ligand TFK(0), however, multiple MD simulations on the TFK(0)/H447I complex reveal that none of the water molecules can be retained in the active site as a "catalytic" water. Taken together our computational studies confirm that TFK(0) is almost inactive in the H447I mutant, and also provide detailed mechanistic insights into the experimental observations.
通过结合从头算量子力学/分子力学（QM/MM）方法和经典分子动力学（MD）模拟，研究了两种抑制剂TFK(+)和TFK(0)与H447I突变型小鼠乙酰胆碱酯酶（mAChE）的反应机制。TFK(+)与H447I突变体的结合可能通过与野生型不同的反应机制进行。一个水分子取代了His447的作用，并作为“电荷中继体”参与键的断裂和形成。与野生型mAChE的情况不同，催化三联体中的保守残基Glu334在反应中充当催化碱。该反应的计算能垒约为8千卡/摩尔。这些预测有待实验验证。然而，对于中性配体TFK(0)，对TFK(0)/H447I复合物的多次MD模拟表明，没有水分子能够作为“催化”水保留在活性位点。综合我们的计算研究证实，TFK(0)在H447I突变体中几乎无活性，同时也为实验观察提供了详细的机理见解。
