The ABEEM/MM Calcium Polarizable Force Field: Parameterization and Applications in Aqueous Solutions and Protein Segments

Reasonably describing the microscopic interaction mechanisms between calcium ions and water as well as ligand proteins is essential for elucidating the structures and functions of calcium proteins. However, capturing the strong polarization between calcium ligands remains a challenge for classical force fields. In this study, we present a fluctuating charge calcium force field for simulations on calcium proteins and aqueous calcium solutions based on Atom-Bond Electronegativity Equalization Method fused into Molecular Mechanics (ABEEM/MM). To reasonably simulate calcium-ligand interactions, model systems comprising calcium ions with water, ethanol, <i>N</i>-methylacetamide, and propionate as ligands were constructed. The ABEEM/MM parameters were then optimized and determined from quantum mechanical (QM) calculations. The performance of the ABEEM/MM model was evaluated by comparison with QM results for the model molecules as well as the Protein Data Bank (PDB) structures of calcium proteins, demonstrating good agreement in reproducing the charge distributions and structures. Molecular dynamics (MD) simulations were conducted on aqueous calcium solutions and protein segments. The ABEEM/MM adequately reproduces the experimentally observed properties, such as the first radial distribution function peak, reaction rate constants, self-diffusion coefficients, etc. The ABEEM/MM model can more effectively capture the dynamic changes in charge distributions and charge transfer processes of aqueous calcium ions under varying coordination numbers. Additionally, MD simulations were performed on calcium proteins using ABEEM/MM alongside nonpolarizable force fields. Comparative analysis with PDB crystal structures revealed that ABEEM/MM gains lower root-mean-square deviations than do the nonpolarizable force fields. This study may pave the way for further investigations into the structures and properties of aqueous electrolyte solutions and metalloproteins using the ABEEM/MM.