Weak yet directional: Supramolecular interactions of thiols unravelled by quantum crystallography

Abstract

Despite being a ubiquitous functional group with biological significance, thiols remain underexplored for their ability to form intermolecular interactions − especially in the solid state. This knowledge gap is largely due to the inadequacy of conventional X-ray crystallography in accurately locating protons involved in such weak thiol hydrogen bonds. Here, we explore weak thiol hydrogen bonds, using X-ray quantum crystallography (QCr) in a series of 31 thiol crystal structures. Neutron diffraction models on three of these structures show a good agreement with corresponding models from Hirshfeld Atom Refinement (HAR). Analyses using HAR models suggest thiol HBs exhibit low pairwise interaction energy (∼ -3 to -15 kJ/mol), significantly lower than that of classical hydrogen bonds. Yet they display clear directionality with hydrogen bond angles in the range 146-164°. Electrostatic potential features around the S–H group from a high-resolution X-ray wavefunction refinement (XWR) model of the drug captopril characterized thiol as a weak hydrogen-bond donor and a moderate acceptor group. Molecular dynamics simulation of thiol drugs in their receptor sites underscores the directional nature of thiol hydrogen bonds preserved even in macromolecular systems. Our results from QCr open new avenues for exploring the role of thiols in molecular recognition, stability, and binding interactions in both molecular materials and biomolecular environments.