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1、AcceptedManuscriptAgeneralacid-generalbasereactionmechanismforhumanbrainaspartoacy‐lase:AQM/MMstudyChenghuaZhang,XiaoqiangLiu,YingXuePII:S2210-271X(11)00598-6DOI:10.1016/j.comptc.2011.11.023Reference:COMPTC532Toappearin:Computational&TheoreticalChemistryReceivedDate:25October2
2、011RevisedDate:9November2011AcceptedDate:9November2011Pleasecitethisarticleas:C.Zhang,X.Liu,Y.Xue,Ageneralacid-generalbasereactionmechanismforhumanbrainaspartoacylase:AQM/MMstudy,Computational&TheoreticalChemistry(2011),doi:10.1016/j.comptc.2011.11.023ThisisaPDFfileofanunedite
3、dmanuscriptthathasbeenacceptedforpublication.Asaservicetoourcustomersweareprovidingthisearlyversionofthemanuscript.Themanuscriptwillundergocopyediting,typesetting,andreviewoftheresultingproofbeforeitispublishedinitsfinalform.Pleasenotethatduringtheproductionprocesserrorsmaybed
4、iscoveredwhichcouldaffectthecontent,andalllegaldisclaimersthatapplytothejournalpertain.Ageneralacid-generalbasereactionmechanismforhumanbrainaspartoacylase:AQM/MMstudyaaa,b,*ChenghuaZhang,XiaoqiangLiu,YingXueaCollegeofChemistry,KeyLaboratoryofGreenChemistryandTechnologyinMinis
5、tryofEducation,SichuanUniversity,Chengdu610064,P.R.ChinabStateKeyLaboratoryofBiotherapy,SichuanUniversity,Chengdu610041,P.R.China----------------------------------------------Correspondingauthor.E-mailaddress:yxue@scu.edu.cnTel:86-28-854183301AbstractAspartoacylaseisacrucialen
6、zymefortheCanavandisease,whichisafatalautosomalrecessivedisorderthataffectsthecentralnervoussystem.Inthiswork,weemployedahybridquantummechanical/molecularmechanical(QM/MM)approachtoinvestigatethereactionmechanismofhumanbrainaspartoacylase.Twopossiblepathwayswereconsidered:thep
7、romoted-waterandtheanhydridemechanisms.Thecalculatedresultsindicatethattheenzymaticreactionproceedsfavourablythroughthepromoted-waterprocesswithGlu178servingasthegeneralbaseandgeneralacid.Thefree-energycalculationssuggestthatthefirstnucleophilicattackstepisrate-determiningwith
8、abarrierof15.9kcal/mol,whichisconsistentwithexperimentalkcatv
