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Unexpected protonation state of Glu197 discovered from simulations of tacrine in butyrylcholinesterase

Abstract

Butyrylcholinesterase (BChE) is actively involved in drug discoveries of many fields for decades. In crystal structure of BChE-tacrine complex, there is an unanticipated formyl-proline molecule resolved very close to tacrine, raising an essential question on how reliable it is to apply the binding pose in crystal structure to analyze related experimental observations, in which no formyl-proline is actually involved. In this study, by performing a series of 100 ns molecular dynamics simulations, we demonstrate that it is safe to employ the structural information from this crystal structure to analyze related experimental observations. Surprisingly, Glu197 needs to be protonated to have the structures simulated appropriately. Note that Glu197 has been commonly considered as deprotonated in diverse analyses due to its low pKa in aqueous solution, in which some interpretations are inconsistent or unclear. Our further investigation show that the protonated Glu197 plays a very important role in preserving His438 within catalytic triad through stabilizing a highly conserved water molecule. Interestingly, catalytic triad and Glu197 have been long recognized for possibly deviating largely from crystal structure, which might be catalytic deficient and is generally considered as the result from difference between crystal and aqueous environment. Here, our results suggest that the large deviations of catalytic triad and Glu197 from crystal structure are caused by inappropriate protonation state of Glu197. This finding shall provide an important clue that has been long missing for the better understanding of BChE related puzzles or even reconsideration of some BChE-catalyzed reaction mechanisms

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Publication details

The article was received on 09 Mar 2018, accepted on 08 May 2018 and first published on 08 May 2018


Article type: Paper
DOI: 10.1039/C8CP01566J
Citation: Phys. Chem. Chem. Phys., 2018, Accepted Manuscript
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    Unexpected protonation state of Glu197 discovered from simulations of tacrine in butyrylcholinesterase

    X. Wan, Y. Yao, L. Fang and J. Liu, Phys. Chem. Chem. Phys., 2018, Accepted Manuscript , DOI: 10.1039/C8CP01566J

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