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The protonation state of Glu202 in acetylcholinesterase
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  • Jiye Wang,
  • Suitian Lai,
  • Yichao Kong,
  • Weixuan Yao,
  • Xiabin Chen,
  • Junjun Liu
Jiye Wang
Zhejiang Police College
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Suitian Lai
Huazhong University of Science and Technology
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Yichao Kong
Hangzhou Normal University
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Weixuan Yao
Zhejiang Police College
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Xiabin Chen
Hangzhou Normal University
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Junjun Liu
Huazhong University of Science and Technology
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Abstract

Acetylcholinesterase (AChE) is the crucial enzyme in the central nervous system. It is the target of various organophosphorus nerve agents and pesticides, and the inhibition of AChE is a therapeutic strategy for the treatment of various neurological-related diseases. The Glu202 is a key residue adjacent to the catalytic His447 and plays important role in catalysis. Although the Glu202 has long been considered as negatively charged in many studies, more and more evidences support a protonated Glu202. However, Glu202 is freely accessible by solvent, and thus it seems more reasonable for Glu202 to majorly take the deprotonated state. In the present work, we carried out a series of molecular dynamics simulations with the Glu202 adopting different protonation states. Our results show that the protonated Glu202 is important in maintaining the key hydrogen bond network that supports the catalytic triad, whereas the deprotonated Glu202 results in the collapse of the key hydrogen bond network which consequently destabilizes the catalytic His447. We also notice that different protonation states of Glu202 merely alters the binding mode of ACh. However, since the catalytic His447 is disrupted if Glu202 is deprotonated, His447 can not facilitate the nucleophilic attack performed by Ser203. Therefore, the catalytic efficiency of ACh hydrolysis should be remarkably decreased if Glu202 is deprotonated. Our findings suggest that, when designing and developing highly active AChE inhibitors or proposing mechanistic hypotheses for AChE-catalyzed reactions, the protonated state of Glu202 should be considered.

Peer review status:UNDER REVIEW

23 May 2021Submitted to PROTEINS: Structure, Function, and Bioinformatics
25 May 2021Assigned to Editor
25 May 2021Submission Checks Completed
05 Jun 2021Reviewer(s) Assigned