To demonstrate the challenge of capturing the Octacid4•guest self-assembly in the act, multiple distinct, independent, unrestricted, unbiased, and classical isobaric-isothermal MD simulations (hereafter shortened to simulations) were performed using the fully deprotonated, apo Octacid4 that was surrounded by 8 neutralizing sodium cations, 10 xylenes to mimic the use of the guest in 10 equivalent excess in the NMR experiment , 60 NaCl molecules to approximate the ionic strength of the experimental conditions , and 2,359 TIP3P water molecules to mimic the experimental aqueous solution . Indeed, no autonomous complexation was observed in any set of 20 14,251.6-ns simulations at 298, 340, 363, or 370 K because the simulation time was many orders of magnitude shorter than the experimentally estimated complexation time for xylene.