Intermolecular Sulfur···Oxygen Interactions: Theoretical and Statistical Investigations.

Intermolecular S center dot center dot center dot O interactions are very common and are important in biological systems, but until recently, the presence of these contacts in protein-ligand systems largely depended on serendipitous discovery instead of rational design. Here we provide insight into the phenomenon of intermolecular S center dot center dot center dot O contacts by focusing on three sulfur-containing aromatic rings. Quantum mechanics is employed to characterize the strength and directionality of the S center dot center dot center dot O interactions and to determine their energy dependence on their geometric parameters. Protein Data Bank mining is performed to systematically determine the occurrence and geometry of intermolecular S center dot center dot center dot O interactions, and several representative examples are discussed. Three typical cases are investigated using a combined quantum mechanics/molecular mechanics approach to demonstrate the potential of these interactions in improving binding affinities and physiochemical properties. Overall, our work elucidates the structures and energy features of intermolecular S center dot center dot center dot O interactions and addresses their use in molecular design.