Date of Award

Spring 2020

Document Type


Degree Name

Doctor of Philosophy (PhD)



First Advisor

Timerghazin, Qadir K.

Second Advisor

Babikov, Dmitri

Third Advisor

Fiedler, Adam T.


S-Nitrosothiols (RSNOs) are ubiquitous biomolecules whose chemistry is tightly controlled in unknown. In this work, we demonstrate, using high-level ab initio and DFT calculations, the ability of RSNOs to participate in intermolecular interactions with electron pair donors/Lewis bases (LBs) via a σ-hole, a region of positive electrostatic potential on the molecular surface at the extension of the N–S bond. Analysis of the nature of the intermolecular interactions in σ-hole bound RSNO-LB complexes shows the dominant role of electrostatic and dispersion interactions. Importantly, σ-hole binding is able to modulate the properties of RSNOs by changing the balance between two chemically opposite (antagonistic) resonance components, R–S+=N–O– (D) and R–S–/NO+ (I), which are, in addition to the main resonance structure R–S–N=O, necessary to describe the unusual electronic structure of RSNOs. σ-Hole binding at the sulfur atom of RSNO promotes the resonance structure D and reduces the resonance structure I, thereby stabilizing the weak N–S bond and making the sulfur atom more electrophilic. On the other hand, increasing the D-character of RSNO by other means (e.g. via N- or O-coordination of a Lewis acid) enhances the σ-hole bonding. Our calculations suggest that in the protein environment a combination of σ-hole bonding of a negatively charged amino acid sidechain at the sulfur atom and N- or O-coordination of a positively charged amino acid sidechain is expected to have a profound effect on the RSNO electronic structure and reactivity.Additionally, protein functionalities are highly dependent on the pKa value of their amino acids. The sequence of deprotonation in thiol containing amino acid side chains determine their nucleophilicity and reactivity. Cysteine as a sulfur containing amino acid is actively involved in the oxidases, reductases and disulfide isomerases through thiol-disulfide exchange reactions. In this study, we investigated the sequence of deprotonation between thiol and carboxylic acid as two active and determining groups in protein structures. This study have been performed in two different types of molecules. First, thiosalicylic acid was considered as an aromatic geminal bifunctional model molecule. The sequence of ionization was analyzed both computationally through DFT calculations and experimentally through UV-vis, NMR and X-ray diffraction measurements. Our experimental analysis were in agreement with our computational analysis confirming the fact that the sequence of deprotonation in bifunctional aromatic thiol-carboxylic acid is not following the classic rules of ionization. Second, we extended our experiment in to aliphatic molecules with vicinal and geminal thiol-carboxylic acid groups. In this part computational studies illustrate untraditional fashion of deprotonation which was incompatible with experimental X-ray diffraction measurements.

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