Chong Lillian T, Bandyopadhyay Pradipta, Scanlan Thomas S, Kuntz Irwin D, Kollman Peter A
Graduate Group in Biophysics and Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94143-2240, USA.
J Comput Chem. 2003 Sep;24(12):1371-7. doi: 10.1002/jcc.10293.
Direct hydroxide attack on the scissile carbonyl of the substrate has been suggested as a likely mechanism for esterase antibodies elicited by phosphonate haptens, which mimic the transition states for the alkaline hydrolysis of esters.1 The unique amidase activity of esterase antibody 43C9 has been attributed to nucleophilic attack by an active-site histidine residue.2 Yet, the active site of 43C9 is strikingly similar to those of other esterase antibodies, particularly 17E8. We have carried out quantum mechanical calculations, molecular dynamics simulations, and free energy calculations to assess the mechanism involving direct hydroxide attack for 43C9. Results support this mechanism and suggest that the mechanism is plausible for other antiphosphonate antibodies that catalyze the hydrolysis of (p-nitro)phenyl esters.
有人提出，氢氧根直接进攻底物的可裂解羰基是膦酸酯半抗原引发的酯酶抗体的一种可能机制，膦酸酯半抗原模拟酯碱性水解的过渡态。1酯酶抗体43C9独特的酰胺酶活性归因于活性位点组氨酸残基的亲核攻击。2然而，43C9的活性位点与其他酯酶抗体的活性位点惊人地相似，尤其是17E8。我们进行了量子力学计算、分子动力学模拟和自由能计算，以评估43C9中涉及氢氧根直接攻击的机制。结果支持了这一机制，并表明该机制对于催化（对硝基）苯酯水解的其他抗膦酸酯抗体也是合理的。
