Quantum mechanics simulations and characterizations of protein-ligand interactions

Protein-ligand interactions play an important role in various biomolecular processes. We have carried out a high-level quantum mechanical analysis of protein-ligand interactions in three biologically important systems.; The first project is to investigate the high binding affinity between streptavidin and biotin. The geometry of the biotin-streptavidin complex was optimized using a hybrid quantum mechanics/molecular mechanics (QM/MM) scheme. The optimized complex enabled a topological analysis of electron density in the framework of Atoms-in-Molecules (AIM) theory and calculations of the intermolecular interaction strengths at a high level of quantum theory. Our simulations attribute the strong binding affinity between biotin and streptavidin to a dominant hydrogen bonding network between the ureido group of biotin and the surrounding residues in the streptavidin. Particularly, the topological analysis provided direct evidence for the hypothesized resonance enhanced polarization of the hydrogen bonding in the biotin-streptavidin complex. Furthermore, the effect of desolvation on the intermolecular interaction energies is found to be important.; The second project is a quantum mechanical analysis of bioactive conformation of Taxol and intermolecular interaction between Taxol and tubulin. The geometry of the Taxol-tubulin complex was optimized using the hybrid quantum mechanics/molecular mechanics (QM/MM) scheme. The resultant bound conformation of Taxol and seven currently known conformers of Taxol were analyzed with ab initio methods. The quantum mechanical calculations present a clear energetic spectrum of seven conformers of Taxol and suggest that the intermolecular interaction between Taxol and histidine 229 of tubulin belong to the class of cation-pi interaction. The conformational analysis of optimized complex leads to our proposal of an induced-fit mode for Taxol-tubulin complex.; The third project is the simulation of interaction between methylated ammonium and the ammonium transporter. The quantum mechanical calculations show that the aromatic cage and Ser219 play a very important role in the intermolecular interaction. The hybrid quantum mechanics/molecular mechanics (QM/MM) simulations demonstrated that tetramethylammonium (TMA) is not able to form as strong a binding to the aromatic cage of the ammonium transporter (AmtB) as methylammonium. Molecular dynamics simulations and quantum mechanical calculations suggest that the energetic cost for dehydration of TMA is much lower than that of MA.