Date of Award
9-6-2024
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Pengfei Li
Abstract
Metalloproteins are ubiquitous in biology, playing crucial roles in diverse processes. Meanwhile, molecular simulations have become an important tool in scientific research. To accurately simulate metalloprotein systems, accounting for polarization and charge transfer effects is required. The fluctuating charge (FQ) model can effectively simulate the charge transfer effect, but the existing models often lack specificity for metalloproteins. In our research, a tailored FQ model for zinc-containing metalloproteins, leveraging the extended charge equilibration (EQeq) scheme, was introduced. CM5 charges were used as the target in our model parameterization, which offers advantages over RESP/CHELPG charges. Most notably, CM5 charges hold independence over conformation or basis set, and avoid unphysical charges for buried atoms, while still accurately reproducing molecular dipoles. Moreover, incorporating a Pauling-bond-order-like correction term between zinc ions and ligating atoms significantly enhances the model's performance. Although trained for four-coordinated zinc sites, our model aptly describes atomic charges across diverse zinc sites. Furthermore, it successfully generates partial charges for metal sites in different zinc-containing metalloproteins, exhibiting performance comparable to RESP charges in molecular dynamics (MD) simulations. Additional tests confirm its efficacy in reproducing CM5 charges under geometric changes. These findings highlight our model's ability to efficiently compute atomic charges for metal sites and accurately simulate charge transfer effects, representing a significant stride toward versatile polarizable force fields for metalloproteins. Following the success of our modeling of zinc-containing metalloproteins, our model was extended towards additional 3d transition metals, namely chromium, manganese, iron, cobalt, and nickel, which are commonly present and utilized in organisms. While using previously optimized parameters for ligand atoms, the metal ion parameters were optimized and found to have excellent transferability. In addition, by using the partial charges determined by our model, we simulated metalloproteins with metal sites containing multiple ions. Again, these charges showed excellent performance and are comparable to that of widely used RESP charges. Expanding the parameterization to include additional metals broadens the applicability of our model to various proteomic metal sites. The 12-6-4 model was developed to consider the polarization effect in ion containing systems. It has been parameterized for various metal ions in aqueous solutions, and it was demonstrated to have superior performance compared to its previous counterpart, the 12-6 model. However, the 12-6-4 model’s efficacy in describing ion-ligand interactions across diverse metal sites remains understudied. In this investigation, we systematically examined biologically relevant zinc-containing metal sites to evaluate the predictive accuracy of both the 12-6 and 12-6-4 models in energetic and structural properties. Magnesium ions (Mg2+) share similar size with zinc ions (Zn2+) but exhibit significantly lower ability to polarize ligands. Our investigation also encompassed evaluation of ion-ligand interaction energies in Mg2+-containing metal sites. By juxtaposing the results obtained for Zn2+ and Mg2+, our analyses offer insights into the performance of the 12-6 and 12-6-4 models in simulating ions. In scientific research, atomic radii are fundamental properties/parameters that can be derived from crystal structures; however, determining van der Waals (VDW) radii of ions poses challenges due to VDW and electrostatic interactions co-existing in crystal structures. As an alternative way, we derived VDW radii of ions through electron density contour analysis. These radii can serve as fundamental parameters in various molecular modeling approaches. Lastly, charge transfer over different types of interactions were analyzed, namely those occurring due to covalent bonds, VDW interactions, ionic bonds, and coordination bonds. By using wavefunction analysis, scans of monomer-monomer interactions were completed, and the insights can be used to facilitate the development of new generation polarizable models.
Recommended Citation
Landry, Luke, "Development and Benchmark of Polarizable Models for Ions" (2024). Dissertations. 4115.
https://ecommons.luc.edu/luc_diss/4115
