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Molecules 2017, 22(11), 1836;

Determination of the Bridging Ligand in the Active Site of Tyrosinase

Yunnan Academy of Tobacco Agricultural Sciences, 33 Yuantong Street, Kunming 650021, China
School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China
Author to whom correspondence should be addressed.
These authors contribute equally to this work.
Received: 29 September 2017 / Revised: 23 October 2017 / Accepted: 25 October 2017 / Published: 28 October 2017
(This article belongs to the Section Computational and Theoretical Chemistry)
PDF [2553 KB, uploaded 31 October 2017]


Tyrosinase is a type-3 copper enzyme that is widely distributed in plants, fungi, insects, and mammals. Developing high potent inhibitors against tyrosinase is of great interest in diverse fields including tobacco curing, food processing, bio-insecticides development, cosmetic development, and human healthcare-related research. In the crystal structure of Agaricus bisporus mushroom tyrosinase, there is an oxygen atom bridging the two copper ions in the active site. It is unclear whether the identity of this bridging oxygen is a water molecule or a hydroxide anion. In the present study, we theoretically determine the identity of this critical bridging oxygen by performing first-principles hybrid quantum mechanics/molecular mechanics/Poisson-Boltzmann-surface area (QM/MM-PBSA) calculations along with a thermodynamic cycle that aim to improve the accuracy. Our results show that the binding with water molecule is energy favored and the QM/MM-optimized structure is very close to the crystal structure, whereas the binding with hydroxide anions causes the increase of energy and significant structural changes of the active site, indicating that the identity of the bridging oxygen must be a water molecule rather than a hydroxide anion. The different binding behavior between water and hydroxide anions may explain why molecules with a carboxyl group or too many negative charges have lower inhibitory activity. In light of this, the design of high potent active inhibitors against tyrosinase should satisfy both the affinity to the copper ions and the charge neutrality of the entire molecule. View Full-Text
Keywords: tyrosinase; active site; bridging ligand; QM/MM-PBSA; inhibitor design tyrosinase; active site; bridging ligand; QM/MM-PBSA; inhibitor design

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Zou, C.; Huang, W.; Zhao, G.; Wan, X.; Hu, X.; Jin, Y.; Li, J.; Liu, J. Determination of the Bridging Ligand in the Active Site of Tyrosinase. Molecules 2017, 22, 1836.

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