Year

2020

Degree Name

Doctor of Philosophy

Department

School of Chemistry and Molecular Bioscience

Abstract

Infrared (IR) spectroscopy is an invaluable tool for the determination of molecular structures, identification of intermediates, and monitoring of chemical reaction in chemistry and biology. However, without any prior chemical insights of the molecule, interpretation of the IR spectra can become complicated by the size of systems and electrostatic interactions in condensed phase. Often, computational vibrational spectroscopy serves as an essential tool in the interpretation of experimental IR spectra.

In Chapter 2, we present a systematic benchmarking study of DFTB3 with two different computational vibrational spectroscopic methods, based on normal mode analysis (NMA) and Fourier transform of the dipole autocorrelation function (FT-DAC). The DFTB3 vibrational frequency results were compared against the experimental data and the theoretical calculations (B3LYP/cc-pVTZ). The empirical scaling factors for DFTB3/NMA, DFTB3-freq/NMA, and DFTB3/FT-DAC methods were 0.9993, 1.0059 and 0.9982, respectively. We also demonstrate the significance of anharmonicity and conformational sampling in vibrational spectroscopic calculations in flexible molecules. The DFTB3/FT-DAC method predicted the anharmonic vibrational peaks more accurately than DFTB3/NMA. The potential limitations of DFTB3 for vibrational spectroscopic calculations and the challenges in assigning the FT-DAC spectral peaks were noted.

In Chapter 3, we estimated the influence of the nuclear quantum effects (NQEs) on the FT-DAC spectra with the thermostated ring-polymer molecular dynamics (TRPMD) simulations. This chapter presents the DFTB3/FT-DAC spectra of deprotonated serine structure with classical MD and TRPMD simulations at room temperature and 100 K. The conformational surface of deprotonated serine was analysed with the 2D potential of mean force calculations. FT-DAC spectral peaks were characterised with the Fourier transform of the localised vibrational mode autocorrelation function (FT- nNAC) and the inter-atomic distance distribution histograms. At room temperature, the quantum effects were not significant, and free energy profile in the classical MD and the TRPMD simulations were very similar. At 100 K, the free energy profile slightly varies between the classic MD and TRPMD simulations. In TRPMD simulations, a marginally stronger internal hydrogen bond network in the conformer-I/II was observed. Overall, the influence of NQEs in the FT-DAC spectra of deprotonated serine was not significant, especially at the room temperature.

In Chapter 4, we extended the DFTB3/FT-DAC method to the solvated systems using the combined DFTB3/MM (MM includes either CGenFF or polarisable Drude oscillator (DO) model) simulations. The FT-DAC spectra of acetophenone, a vibrational chromophore, was calculated in a series of non-polar and polar solvents as well as solvent mixtures. Both DFTB3/MM simulations predicted the carbonyl stretch peak close to the experimental frequencies in the non-hydrogen bond-forming solvents. However, we observed an overestimation of the solvent-induced red-shift in the hydrogen bondforming solvents. From the microsolvation studies, we found that the overestimation of the red-shift in DFTB3/MM simulations was due to the increased number of solutesolvent hydrogen bonds. In DFTB3/CGenFF simulations, the carbonyl peak was deviated by 57 cm-1 from the experimental frequency. The DFTB3/DO simulations partially recovered the carbonyl peak, deviated only by 26 cm-1. We also investigated the effect of solvent-induced electric fields on vibrational frequency shifts, known as the vibrational Stark effect. Linear correlations between the solvent-induced electric fields and the vibrational probe’s frequency shifts were found. Apart from extending the FT-DAC method to condensed phase systems, this study highlights the importance of including explicit polarisation in QM/MM simulations. Our current results indicate that further optimisation is needed for computational vibrational spectroscopy for condensed phase systems.

In Chapter 5, we reviewed the importance of the polarisable force fields in biomolecular systems. The quality of biomolecular simulations critically depends on the accuracy of the force field used to calculate the potential energy of the molecular configurations. Currently, most simulations employ non-polarisable force fields, which describe electrostatic interactions as the sum of Coulombic interactions between fixed atomic charges. Polarisation of these charge distributions is incorporated only in a mean-field manner. In the past decade, extensive efforts have been devoted to developing simple, efficient, and yet generally applicable polarisable force fields for biomolecular simulations. In this chapter, we summarise the latest developments in accounting for key biomolecular interactions with polarisable force fields and applications to address challenging biological questions. In the end, we provide an outlook for future development in polarisable force fields.

In Chapter 6, we summarise the work presented in this thesis and outline my personal outlook for future development on these topics.

FoR codes (2008)

0301 ANALYTICAL CHEMISTRY, 0304 MEDICINAL AND BIOMOLECULAR CHEMISTRY, 0306 PHYSICAL CHEMISTRY (INCL. STRUCTURAL), 0307 THEORETICAL AND COMPUTATIONAL CHEMISTRY

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Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.