Redox Potentials of Disulfide Bonds in LOXL2 Studied by Nonequilibrium Alchemical Simulation

Lirui Lin; Haiying Zou; Wenjin Li; Li-Yan Xu; En-Min Li; Geng Dong

doi:10.3389/fchem.2021.797036

Redox Potentials of Disulfide Bonds in LOXL2 Studied by Nonequilibrium Alchemical Simulation

Front Chem. 2021 Dec 14:9:797036. doi: 10.3389/fchem.2021.797036. eCollection 2021.

Authors

Lirui Lin^{1

2}, Haiying Zou^{1

3}, Wenjin Li⁴, Li-Yan Xu^{3

5}, En-Min Li^{1

3}, Geng Dong^{1

2}

Affiliations

¹ Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China.
² Medical Informatics Research Center, Shantou University Medical College, Shantou, China.
³ Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, China.
⁴ Institute for Advanced Study, Shenzhen University, Shenzhen, China.
⁵ Cancer Research Center, Shantou University Medical College, Shantou, China.

Abstract

Lysyl oxidase-like 2 (LOXL2) is a metalloenzyme that catalyzes the oxidative deamination ε-amino group of lysine. It is found that LOXL2 is a promotor for the metastasis and invasion of cancer cells. Disulfide bonds are important components in LOXL2, and they play a stabilizing role for protein structure or a functional role for regulating protein bioactivity. The redox potential of disulfide bond is one important property to determine the functional role of disulfide bond. In this study, we have calculated the reduction potential of all the disulfide bonds in LOXL2 by non-equilibrium alchemical simulations. Our results show that seven of seventeen disulfide bonds have high redox potentials between -182 and -298 mV and could have a functional role, viz., Cys573-Cys625, Cys579-Cys695, Cys657-Cys673, and Cys663-Cys685 in the catalytic domain, Cys351-Cys414, Cys464-Cys530, and Cys477-Cys543 in the scavenger receptor cysteine-rich (SRCR) domains. The disulfide bond of Cys351-Cys414 is predicted to play an allosteric function role, which could affect the metastasis and invasion of cancer cells. Other functional bonds have a catalytic role related to enzyme activity. The rest of disulfide bonds are predicted to play a structural role. Our study provides an important insight for the classification of disulfide bonds in LOXL2 and can be utilized for the drug design that targets the cysteine residues in LOXL2.

Keywords: LOXL2; alchemical method; disulfide bond; non-equilibration simulation; redox potential.