Probing the role of zinc ion in metallo-β-lactamase inhibitor binding by using multiple molecular dynamics simulations

The hydrolysis of the β-lactam ring of antibiotics mediated by Verona Integrin-encoded metallo-β-lactamase 2 (VIM-2) in the presence of two zinc ions (Zn1 and Zn2) leads to significant resistance toward β-lactam antibiotics. Here, multiple molecular dynamics (MD) simulations were performed on two systems, including VIM-2 with two Zn1 and Zn2 ions and a single Zn1 ion, to unravel the molecular mechanism of conformational changes of VIM-2 induced by the removal of Zn2 ion and the role of Zn2 in the binding of the VIM-2 inhibitor (ANT431). The results suggest that the binding of two zinc ions stabilizes the two flexible L3 and L10 loops constituting the binding site for ANT431, whereas in the presence of a single Zn1 ion, the L3 and L10 loops exhibit an enhanced conformational flexibility. Further structural analyses reveal that the binding of two zinc ions maintains a closed conformation of ANT431 binding site, while the ANT431 binding site mainly exists as an open conformation without the Zn2 ion. Consistently, ANT431 remains stable in the active site of VIM-2 in the presence of two zinc ions, while it escapes from the active site in the presence of a single Zn1 ion. We anticipate that our results may offer useful dynamical information pertaining to conformational changes of VIM-2 for the design of potent and selective inhibitors to alleviate drug resistance of VIM-2 toward antibiotics. • Molecular dynamics simulations of zinc-bound metallo-β-lactamase 2. • The Zn2 ion stabilizes the conformational dynamics of L3 and L10 loops. • The Zn2 ion stabilizes the binding of ANT431 to VIM-2.