Year: 2026
Type: preprint
Abstract: Histidine side chains are prevalent in binding sites and can engage in stacking interactions with heterocyclic ligand components. However, efforts to harness these interactions for molecular recognition are often hampered by an incomplete understanding of the factors that control the strength and preferred geometries of these interactions. To this end, we provide a comprehensive computational analysis of stacked dimers of druglike heterocycles with the three protomers of the histidine side chain. The data show that the strengths of these stacking interactions span a considerable range, offering a potentially fruitful means of modulating binding. While the strength of stacking interactions with the neutral Nδ−H and Nε−H tautomers are strongly correlated, stacked dimers of aromatic heterocycles with the imidazolium form follow a qualitatively different trend. Moreover, the impact of placing heteroatoms at a given position depends on the protomeric state, highlighting potential challenges in designing heterocycles to stack strongly with binding site histidine side chains. Ultimately, we provide simple predictive models of the maximum possible stacking strength of mono- or bicyclic heterocycles with the three protomers of histidine based on readily computed heterocycle descriptors. We also interpret these results within the framework of our recently introduced model of heteroatom effects in parallel-displaced stacking interactions (J. Am. Chem. Soc. 2025, 147, 32273), which provides a means of predicting the preferred orientation of heterocycles stacked with histidine.
Source: ChemRxiv
Authors: Lily C. Barnett, Khue U. Do, Steven E. Wheeler
Institution: University of Georgia
Language: English
Subfield: Physical and Theoretical Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7220468043