Simulating Metal-Imidazole Complexes

06 May 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


One commonly observed binding motif in metalloproteins involves the interaction between a metal ion and histidine's imidazole sidechains. Although previous imidazole-M(II) parameters established the flexibility and reliability of the 12-6-4 Lennard-Jones (LJ)-type nonbonded model by simply tuning the ligating atom’s polarizability, they have not been applied to multiple-imidazole complexes. To fill this gap, we systematically simulate multiple-imidazole complexes (ranging from one to six) for five metal ions (Co(II), Cu(II), Mn(II), Ni(II), and Zn(II)) which commonly appear in metalloproteins. Using extensive (40ns per PMF window) sampling to assemble free energy association profiles (using OPC water and standard HID imidazole charge models from AMBER) and comparing them to DFT calculations, a new set of parameters was developed to focus on energetic and geometric features of multiple-imidazole complexes. The obtained free energy profiles agree with the experimental binding free energy and DFT calculated distances. Further investigation of the simulations revealed the existence of ligand-ligand hydrogen bonds and partial π-stacking while one ligand dissociates from the complex. To validate our model, we show that we can close the thermodynamic cycle for metal-imidazole complexes with up to six imidazole molecules in the first solvation shell. Given the success in closing the thermodynamic cycles, we then used the same extended sampling method for six other metal ions (Ag(I), Ca(II), Cd(II), Cu(I), Fe(II), and Mg(II)) to obtain new parameters. Since these new parameters can reproduce the one-imidazole geometry and energy accurately, we hypothesize that they will reasonably predict the binding free energy of higher-level coordination numbers. Hence, we did not extend the analysis of these ions up to six imidazole complexes. Overall, the results shed light on metal-protein interactions by emphasizing the importance of ligand-ligand interaction and metal-π-stacking within metalloproteins.


Transition Metal Ion
Imidazole Cluster
Extended Sampling
12-6-4 LJ Nonbonded Model

Supplementary materials

Extra PMFs and thermodynamic cycles
All PMFs and thermodynamic cycles for different metal-imidazole complexes.

Supplementary weblinks


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