Divalent Sulfur mediated interactions in proteins architecture, stability and molecular recognition

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.