کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2581584 | 1561653 | 2008 | 4 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Acetylcholinesterase: Mechanisms of covalent inhibition of H447I mutant determined by computational analyses
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
علوم محیط زیست
بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
The reaction mechanisms of two inhibitor TFK+ and TFK0 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 8Â kcal/mol. These predictions await experimental verification. In the case of the neutral ligand TFK0, however, multiple MD simulations on the TFK0/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 TFK0 is almost inactive in the H447I mutant, and also provide detailed mechanistic insights into the experimental observations.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Chemico-Biological Interactions - Volume 175, Issues 1â3, 25 September 2008, Pages 196-199
Journal: Chemico-Biological Interactions - Volume 175, Issues 1â3, 25 September 2008, Pages 196-199
نویسندگان
Y.H. Cheng, X.L. Cheng, Z. RadiÄ, J.A. McCammon,