Noncovalent interactions involving sulfur atoms play essential roles in protein structure and function by significantly contributing to the protein and peptide stability, the overall folding, and biological activity. Sulfur being a highly polarizable atom with filled 3p and empty 3d orbitals participates in strong van der Waals interactions as well as hydrogen bonding, electrostatic interactions, and hydrophobic effect and the impact of these interactions on molecular recognition and drug design is profound. For instance, hydrogen bonding has a fundamental role in secondary structure motifs and sulfur atoms have been known to accept and donate hydrogen bonds. Moreover, S---π, S---X, and S---C=O interactions are important contributors to controlling the overall protein framework. Despite, the unique attributes of noncovalent interactions, they are being unappreciated. Although, only one of these interactions contributes only a few kcals energetically, as the system size grows this contribution increases dramatically. Understanding the nature of these noncovalent interactions involving sulfur atoms could pave the way for drug design and development. Therefore, we chose naturally occurring complex molecules Glycothiohexide α and its close structural analog Nocathiacin I as our model systems and deeply investigate the intramolecular sulfur contacts that are important for the structures by quantum chemical calculations.<br/>Glycothiohexide α and Nocathiacin I are sulfur-containing polycyclic thiopeptide antibiotics with fascinating bioactivities. They are highly potent against gram-positive bacteria and have features of both small drugs and proteins. We validate our structures by computational NMR calculations. We identify the strength of the intramolecular non-covalent interactions involving sulfur atoms both quantitatively and qualitatively by natural bond orbital (NBO) analysis, non-covalent interaction (NCI) analysis, and energy decomposition (EDA) analysis as measures to understand which type of interaction contributes more to the overall stability.

Noncovalent interactions involving sulfur atoms in thiopeptide antibiotics glycothiohexide α and nocathiacin I

ACS Spring 2022

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