Host-guest complexation of (pyridinyltriazolylthio) acetic acid with cucurbit[n]urils (n=6,7,8): Molecular calculations and thermogravimetric analysis

Cucurbiturils are cagelike macrocyclic molecules that can form strong host–guest inclusion complexes, offering remarkably higher selectivity over conventional macrocycles towards guests with particular sizes and shapes. Here we use a combination of molecular docking, semiempirical quantum-chemical (PM6, PM7) and high-level DFT calculations along with all-atom molecular dynamics (MD) simulations to characterize 1:1 host-guest complexation between the cucurbit[n]urils (CB[n], where n=6-8) and biologically active 2-[[5-(4-pyridinyl)-4H-1,2,4-triazol-3-yl]thio]acetic acid (PTTA). While the molecular docking and the semiempirical calculations suggest that PTTA favors inserting into larger size cavities of CB[7] and CB[8], the classical OPLS-AA MD simulations of the potential of the mean force (PMF) in an aqueous solution demonstrate the favorable free binding energy of PTTA with all three studied CB[n] (n=6-8). These findings were further collaborated by refining the binding energy of the MD-derived PTTA-CB[n] structures by the high-level dispersion-corrected DFT calculations. Our combined MD/DFT approach provides the detailed host-guest complexation mechanism and suggests that the stability of the host-guest inclusion complex of PTTA with CB[n]s decreases in the order CB[6]>CB[7]>CB[8]. Finally, the formation of the stable inclusion complex of PTTA with CB[6] was validated by thermogravimetric analysis and differential scanning calorimetry measurements, pointing out that low-level quantum-chemical methods might be unable to capture the correct thermodynamics of host-guest supramolecular structures based on cucurbituril macrocycles.