Molecular dynamics simulations of molecular binding in materials and biological systems
Creators: name: Wu, Yuxuan
Publisher: name: No Publisher Supplied
Year: 2023

description: My PhD work in computational chemistry focuses on using molecular dynamics (MD) simulations to study molecular binding in materials and biological systems. In this thesis, three computational projects will be discussed: characterization of adsorptive desulfurization in metal-organic frameworks (MOFs), free energy simulations of the binding of flavonoids and their derivatives in a transcriptional regulator TtgR, and the investigation of analyte adsorption on metal surfaces in surface-enhanced Raman scattering (SERS) measurements. MOFs are excellent materials to remove organosulfur contaminants from petroleum fuels. However, unlike their gas adsorption properties, there are no clear rules for the desulfurization performance of MOFs in liquid fuels. I used MOF-505, UMCM-150 and MOF-177 as representative materials and performed MD simulations to investigate the interactions between the MOFs and two commonly observed organosulfur compounds, benzothiophene (BT) and 4,6-dimethyldibenzothiophene (DMDBT), in the absence and presence of a model fuel isooctane. From the simulations, I showed that the conjugated organosulfur compounds bind to the MOF linkers through $pi$ stacking and the difference in the intermolecular forces allowed for their separation from the isooctane solvents. The chemical nature of the molecules and the size matching effect combined to modulate the adsorption geometries, translational and rotational movements and uptake efficiencies of BT and DMDBT. These findings revealed the key interactions that drive the binding of BT and DMDBT in the three MOFs, which will aid the design of materials for efficient adsorptive desulfurization to produce clean fuels. TtgR is a transcriptional regulator in bacteria that binds and senses various antibacterial chemicals, including flavonoids. It modulates the activity of an efflux pump TtgABC to expel the hazardous chemicals, and thus contributing to the drug resistance in bacteria. To investigate its interactions with the drug molecules, I performed MD simulations and thermodynamic integration calculations to obtain the binding free energies of seven flavonoids and their derivatives in the active site of TtgR. The simulations revealed that the binding involved hydrogen bonding, $pi$ stacking, cation-$pi$, methyl-$pi$, electrostatic and van der Waals interactions. I further demonstrated how the hydroxyl groups on the phenyl ring and a higher degree of oxidation can enhance the binding affinity. These results indicated that the aromatic and hydroxyl moieties are key components in the ligand recognition events of TtgR. The findings will lead to a better understanding of chemical binding in TtgR and inform the designs of new drugs that are less susceptible to resistance. In addition to carrying out my own projects, I collaborated with the Fabris group at Rutgers University and computationally studied the adsorption of analytes on metal surfaces in their SERS experiments. In the first collaboration project, the Fabris group developed a portable SERS device for rapid identification and quantification of opioid drugs. I performed MD simulations to investigate the molecular adsorption mechanism for multiple drugs on the nanoparticle surface. Specifically, simulations were conducted for the adsorption of fentanyl, heroin, THC, and norfentanyl on silver nanoparticles, and I revealed that the binding arised from charge transfer, aromatic–metal and dispersion interactions at the molecule–metal interface. The most favorable SERS response of fentanyl among all the drug molecules was explained by its strongest adsorption on the silver surface. In the second collaboration, I worked with a group member Zelin Wang to investigate the adsorption of 4-ATP, TP, and CV on gold nanostars and showed that the analyte concentration strongly influenced their adsorption orientations, in good agreement with the observations from the SERS experiments.