... In this work, to explore effect of binding of zinc ions on conformation changes of SPM-1, three systems, including SPM-1 without zinc ions (free SPM), SPM-1 with single zinc ion and double zinc ions, were chosen to realize our aims. Despite great success of molecular dynamics (MD) simulations in investigating conformational changes of targets caused by ligand bindings (Chen et al., 2019c;De Oliveira dos Santos Soares, Bortot, van der Spoel, & Caliri, 2017;Fischer, van der Spoel, Polêto, & Steuer, 2018;Guo, Han, Luo, & Chen, 2017;Hou, Zhang, Wang, & Wang, 2009;Hu, Ma, & Wang, 2017;Lou, Li, & Han, 2015;Peng et al., 2018;Shi et al., 2018;Song, Luo, & Chen, 2017;Song et al., 2019;Srinivasan & Rajasekaran, 2018;Sun et al., 2014;Tian et al., 2019;Tu et al., 2019;Yang, Zhang, & Han, 2010;Zhang et al., 2017;Zhao, Dong, & Zheng, 2018), conventional MD (cMD) simulations possibly make the simulated conformations fall into local minimum space, which will lead to insufficient conformational sampling. Compared to cMD simulations, replica-exchange molecular dynamics (REMD) simulations, including temperature-replica exchange molecular dynamics (REMD) (Jiang & Roux, 2010;Jiang, Thirman, Jo, & Roux, 2018;Patriksson & van der Spoel, 2008) and replica exchange with solute tempering (REST) (Cole, Tirado-Rives, & Jorgensen, 2014;Huang et al., 2007;Liu, Kim, Friesner, & Berne, 2005;Terakawa, Kameda, & Takada, 2011;Wang, Friesner, & Berne, 2011), can efficiently improve the conformational sampling. ...