Date of Award


Publication Type

Doctoral Thesis

Degree Name



Chemistry and Biochemistry

First Advisor

Gauld, J.



Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.


Sulfur-containing molecules are chemically and functionally versatile compounds, exemplified by their diverse roles from enzymatic processes to organic synthesis and drug design. With the goal of gaining detailed and deeper insights into the chemistry of such species, multi-scale computational modeling techniques we have applied in this work. Chapter 1 provides a brief summary of the importance of sulfur, its functionality, and reactivity in biological systems including catalytic environments such as enzymes. In Chapter 2, an overview of the key features of the common and contemporary computational approaches is explained briefly. In Chapter 3, systematic benchmark studies are performed to determine reliable and accurate structures as well as thermochemical data for a series of bio-relevant polysulfur/ selenium-containing compounds. Of the variety of DFT functionals and Pople basis sets examined, the ωB97XD/6-311G(2d,p) level of theory is found to generally give the most accurate and reliable results. Furthermore, S—S bond lengths are more sensitive to the choice of basis set than those containing Se. Comparison of the proton affinities and gas-phase basicities of thiols and their corresponding persulfide derivatives indicates that extending the sulfur chain decreases their values, suggesting that polysulfur species exist as deprotonated species in biological systems. In Chapter 4, the roles of solvent choice on the possible mechanisms of formation of sulfonamides via the reaction of SO2 and N-tosyl hydrazone using DFT-based methods in combination with implicit and hybrid implicit/explicit solvation models is examined. The results indicate that solvent-solute interactions can play critical roles in such reactions. Of the solvents considered, DMSO and piperidine are found to be the most effective (i.e., actively involved) facilitating sulfonamide bond formation. Applying DFT and conventional ab initio methods, Chapter 5 examines the formation of SO2-containing molecules including sulfones, sulfonamides, and sulfamides via the radical-based reaction of SO2 with a systematic series of xiamycin-inspired aromatic C- and N-centered radicals. A preference for C–S(O2) vs. N–S(O2) bond formation is observed with formation of sulfones being thermodynamically preferred to sulfamides. Also, of the DFT functionals used, the M06-2X functional was shown to be most reliable for providing optimized geometries and relative energies of the SO2-containing species examined. In Chapter 6, the formation of a range of possible HNO-derived post-translational modifications of cysteinyl and cysteinyl persulfide was examined using DFT-based methods. It is shown that the formation of the initial -X-NHOH (X=S, S-S) containing intermediate is independent of the residues position in the peptide while their subsequent reaction and final PTM formed is dependent on the residues position. More specifically, reaction of HNO with N-terminus or internal residues leads to formation of disulfide or sulfonamide (e.g., Cys-SS-Cys or Cys-S(O)-NH2) via rearrangement and nucleophilic substitutions, respectively. Meanwhile, Cys-X-NH2 derived from C-terminus peptide leads to Cys-X-OH formation through the intermediacy of a 5- or 6-membered cyclic intermediates in cystenyl and cystenyl persulfide, respectively. In Chapter 7 we examine the active site, substrate binding, and catalytic mechanism of the bacterial Ni(II)-dimethylsulfoniopropionate (DMSP) lyase (DddK) enzyme. The findings show that two active site tyrosyls (Tyr64 and 122) play significant roles in substrate binding, with Tyr64 also acting as a Lewis base to initiate the β-concerted elimination reaction to form the dimethyl sulfide product. In Chapter 8 we examine, using a multi-scale computational approach, a possible disulfidesulfenylamide shuttling mechanism in the active site of DAH7PS enzyme. The results imply the key role of the metal ion (Mn(II)) and acidic environment in the potential interconversion between these conformations. Our findings infer that the preference of the cyclic sulfenylamide conformation to disulfide in the enzyme active site switches to the preference of disulfide to cyclic sulfenylamide conformation in the absence of metal ions and/or providing an acidic environment.