Free energy profiles of cocaine esterase-cocaine binding process by molecular dynamics and potential of mean force simulations

Yuxin Zhang; Xiaoqin Huang; Keli Han; Fang Zheng; Chang-Guo Zhan

doi:10.1016/j.cbi.2016.05.011

Free energy profiles of cocaine esterase-cocaine binding process by molecular dynamics and potential of mean force simulations

Chem Biol Interact. 2016 Nov 25;259(Pt B):142-147. doi: 10.1016/j.cbi.2016.05.011. Epub 2016 May 6.

Authors

Yuxin Zhang¹, Xiaoqin Huang², Keli Han³, Fang Zheng⁴, Chang-Guo Zhan⁵

Affiliations

¹ State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Science, Zhongshan Road 457, Dalian 116023, PR China; Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
² Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
³ State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Science, Zhongshan Road 457, Dalian 116023, PR China.
⁴ Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
⁵ Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA. Electronic address: zhan@uky.edu.

Abstract

The combined molecular dynamics (MD) and potential of mean force (PMF) simulations have been performed to determine the free energy profile of the CocE)-(+)-cocaine binding process in comparison with that of the corresponding CocE-(-)-cocaine binding process. According to the MD simulations, the equilibrium CocE-(+)-cocaine binding mode is similar to the CocE-(-)-cocaine binding mode. However, based on the simulated free energy profiles, a significant free energy barrier (∼5 kcal/mol) exists in the CocE-(+)-cocaine binding process whereas no obvious free energy barrier exists in the CocE-(-)-cocaine binding process, although the free energy barrier of ∼5 kcal/mol is not high enough to really slow down the CocE-(+)-cocaine binding process. In addition, the obtained free energy profiles also demonstrate that (+)-cocaine and (-)-cocaine have very close binding free energies with CocE, with a negligible difference (∼0.2 kcal/mol), which is qualitatively consistent with the nearly same experimental K_M values of the CocE enzyme for (+)-cocaine and (-)-cocaine. The consistency between the computational results and available experimental data suggests that the mechanistic insights obtained from this study are reasonable.

Keywords: Binding process; Cocaine; Energy barrier; Esterase.

MeSH terms

Binding Sites
Carboxylic Ester Hydrolases / chemistry
Carboxylic Ester Hydrolases / metabolism*
Cocaine / chemistry
Cocaine / metabolism*
Molecular Dynamics Simulation
Protein Binding
Thermodynamics

Substances

Carboxylic Ester Hydrolases
cocaine esterase
Cocaine

Abstract

MeSH terms

Substances

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