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

Cucurbiturils are cage-like 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]s (n = 6-8). These findings were further examined 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.