Quantum Chemical Calculation Of Bio-molecular NMR Spectroscopy And Force Field Development For Metal-protein

Recently, in the wake of developments in theory and computer science, quantum chemistry calculation is more and more used to explore the structure and function of bio-molecules. However, the quantum calculation needs massively computer resources, thus cannot be applied on large systems like proteins directly. Therefore, people have to develop variously approximation methods to expand its application limits. The main work of this study completed as follows:first, we introduced the solvent effect into the AF-QM/MM (Automated Fragmentation Quantum Mechanics/Molecular Mechanics) model based on Divide&Conquer theory, which can calculate the protein chemical shifts using quantum chemistry method, and then, we proposed a new force field for study of zinc protein:QPCT (Non-bonded quantum-calibrated polarizable-charge transfer force field).In the AF-QM/MM approach, the entire protein is divided into non-overlapping fragments termed core regions. The residues within a certain range from the core region are included in the buffer region. Both the core and the buffer regions are treated by quantum mechanics, while the remainder of the protein is described using an empirical point-charge model to account for the electrostatic effect. Each core-centric (core+buffer) QM/MM calculation is carried out separately and only the chemical shifts of the atoms in the core region are extracted from individual QM/MM calculation. By using PB model and explicit waters, the solvation effects are also included in AF-QM/MM method. Using this scheme, we can divide the entire protein into undependable fragments, thus the calculation is totally linear-scaling. Our calculated chemical shifts of1H and13C and15N atoms of proteins are in remarkable agreement with experimentally measured values and also can be used to predict and refine protein structures. The applications may also be extended to more general biological systems, such as nonstandard residues, metalloproteins, protein-ligand, protein-DNA/RNA and membrane protein-lipid complexes.Although making great improvement over the past two decades, most today’s force fields do not always have appropriate parameters for metal atoms, which has become a practical obstacle for the molecular modeling studies of metalloproteins. In the current work, the QPCT force field was proposed to capture the polarization and charge transfer contributions to the interatomic interactions for zinc-proteins. These parameters were validated extensively in molecular dynamic simulations of hydration shell of zinc ion and five proteins containing most common zinc-binding sites as well as one protein-ligand complex. The calculated results of QPCT show excellent agreement with the experimental measurements and QM/MM MD simulations, demonstrating that the present approach can provide enough accuracy to maintain the integrity of the zinc binding pocket during extended molecular dynamic simulations. The QPCT method is easily to parameterize and transfer to other systems having the same coordinate geometry, and it can also be extended to study the interaction of other metals that have large charge transfer and polarization effects.