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Open AccessArticle

An Ab Initio QM/MM Study of the Electrostatic Contribution to Catalysis in the Active Site of Ketosteroid Isomerase

by Xianwei Wang 1,2 and Xiao He 2,3,*
1
College of Science, Zhejiang University of Technology, Hangzhou 310023, Zhejiang, China
2
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
3
NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, China
*
Author to whom correspondence should be addressed.
Molecules 2018, 23(10), 2410; https://doi.org/10.3390/molecules23102410
Received: 28 August 2018 / Revised: 16 September 2018 / Accepted: 17 September 2018 / Published: 20 September 2018
The electric field in the hydrogen-bond network of the active site of ketosteroid isomerase (KSI) has been experimentally measured using vibrational Stark effect (VSE) spectroscopy, and utilized to study the electrostatic contribution to catalysis. A large gap was found in the electric field between the computational simulation based on the Amber force field and the experimental measurement. In this work, quantum mechanical (QM) calculations of the electric field were performed using an ab initio QM/MM molecular dynamics (MD) simulation and electrostatically embedded generalized molecular fractionation with conjugate caps (EE-GMFCC) method. Our results demonstrate that the QM-derived electric field based on the snapshots from QM/MM MD simulation could give quantitative agreement with the experiment. The accurate calculation of the electric field inside the protein requires both the rigorous sampling of configurations, and a QM description of the electrostatic field. Based on the direct QM calculation of the electric field, we theoretically confirmed that there is a linear correlation relationship between the activation free energy and the electric field in the active site of wild-type KSI and its mutants (namely, D103N, Y16S, and D103L). Our study presents a computational protocol for the accurate simulation of the electric field in the active site of the protein, and provides a theoretical foundation that supports the link between electric fields and enzyme catalysis. View Full-Text
Keywords: electric field; hydrogen-bond network; vibrational Stark effect; enzyme catalysis electric field; hydrogen-bond network; vibrational Stark effect; enzyme catalysis
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MDPI and ACS Style

Wang, X.; He, X. An Ab Initio QM/MM Study of the Electrostatic Contribution to Catalysis in the Active Site of Ketosteroid Isomerase. Molecules 2018, 23, 2410.

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