Conformation Changes Associated with the Formation and Activation of Lysine Tyrosylquinone of LOXL2 Studied by Metadynamics Simulation.

Lysyl oxidase‐like 2 (LOXL2) is a Cu2+‐dependent amine oxidase that catalyzes the oxidative deamination of lysine residues of elastin and collagen to generate aldehyde groups. In the active state of LOXL2, its conserved catalytic domain has a lysine tyrosylquinone (LTQ) cofactor and a copper ion. LTQ is post‐translationally derived from Lys653 and Tyr689 of LOXL2. In this study, well‐tempered metadynamics simulations are used to investigate the conformation modulation from the inactive state to active state and obtain the free energy landscape. Interestingly, the simulations show that LTQ precursor residues cannot get close in Zn2+−bound LOXL2, whereas the copper ion binding triggers a conformation change to form an optional structure for LTQ biosynthesis. It is found that a prominent loop, consisting of residues 654–658, hinders the formation of LTQ in Zn2+−LOXL2 by preventing Lys653 from moving into active site of LOXL2, whereas this loop is relatively flexible in Cu2+−LOXL2. After the formation of LTQ, it needs to be activated by adjusting its position to be exposed to the solvent, thus allowing it to react with its substrate proteins. The results indicate that this process involves an intermediate state and that the activation of LTQ overcomes an energy barrier of 5.9 kcal mol−1. [ABSTRACT FROM AUTHOR]