Abstract:
Non-covalent interactions are crucial for protein folding and stability.
Traditionally, hydrogen bonding (H-bond), hydrophobic, and stacking interactions are
well studied in biomolecules. Divalent Sulfur (S), which is present in small organic
molecules, ligands and in proteins, also has the ability to form non-covalent
interactions called chalcogen interaction (Ch-bond) and H-bond. In general, Ch-bond
is made between S and nucleophiles. However, these S-mediated interactions
remain unnoticed in biomolecules. In this study, we addressed the role of Ch-bond in
protein structure and its effect on protein stability through extensive computational
and bioinformatics analyses of high-resolution protein structures available in Protein
Data Bank (PDB). This study gives unprecedented insights into the role of S present
in methionine and cysteine on protein architecture. Here we showed that, H- and Ch-
bond made by S can involve in capping of terminus of the α-helices. Along with this,
we also showed that Ch-bond can stabilize regular and non-regular secondary
structural elements of proteins. In addition to the computational analyses, we also
carried out biophysical and biochemical experiments to find role of Ch-bond in
protein-ligand interaction, if any. For this purpose we selected methionyl-tRNA
synthase (MetRS) as a model system. We found that, disruption of Ch-bond caused
four-fold reduction in binding of the methionine to MetRS, demonstrating the
importance of Ch-bond in ligand binding.
