New ultra-high affinity host-guest complexes of cucurbit[7]uril with bicyclo[2.2.2]octane and adamantane guests: Thermodynamic analysis and evaluation of M2 affinity calculations Sarvin Moghaddam † , Cheng Yang § , Mikhail Rekharsky § , Young Ho Ko ¶ , Kimoon Kim ¶ , Yoshihisa Inoue *,§ , and Michael K. Gilson *,†,‖ † Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850, USA § PRESTO (JST) and Department of Applied Chemistry, Osaka University, Yamada-oka, Suita 565-0871, Japan ¶ National Creative Research Initiative Center for Smart Supramolecules and Department of Chemistry, Pohang, University of Science and Technology, San 31 Hyojadong, Pohang 790-784, Republic of Korea Abstract A dicationic ferrocene derivative has previously been shown to bind cucurbit[7]uril (CB[7]) in water with ultra-high affinity (ΔG o = −21 kcal/mol). Here, we describe new compounds that bind aqueous CB[7] equally well, validating our prior suggestion that they, too, would be ultra-high affinity CB[7] guests. The present guests, which are based upon either a bicyclo[2.2.2]octane or adamantane core, have no metal atoms, so these results also confirm that the remarkably high affinities of the ferrocene-based guest need not be attributed to metal-specific interactions. Because we used the M2 method to compute the affinities of several of the new host-guest systems prior to synthesizing them, the present results also provide for the first blinded evaluation of this computational method. The blinded calculations agree reasonably well with experiment and successfully reproduce the observation that the new adamantane-based guests achieve extremely high affinities, despite the fact that they position a cationic substituent at only one electronegative portal of the CB[7] host. However, there are also significant deviations from experiment, and these lead to the correction of a procedural error and an instructive evaluation of the sensitivity of the calculations to physically reasonable variations in molecular energy parameters. The new experimental and computational results presented here bear on the physical mechanisms of molecular recognition, the accuracy of the M2 method, and the usefulness of host-guest systems as test-beds for computational methods. * To whom correspondence may be addressed: inoue@chem.eng.osaka-u.ac.up, mgilson@ucsd.edu. ‖ Present address: Skaggs School of Pharmacy and Pharmaceutical Sciences, 9500 Gilman Drive, MC 0736, La Jolla, CA, 92093, USA. Supporting Information Available Synthetic procedures, associated NMR and mass spectra, and calorimetric titration data for guests A2, B2, B5 and B11 with CB[7]. Complete reference 10 . Maximally stable computed conformations of the free molecules and bound complexes. This information is available free of charge via the Internet at http://pubs.acs.org/. NIH Public Access Author Manuscript J Am Chem Soc. Author manuscript; available in PMC 2012 March 16. Published in final edited form as: J Am Chem Soc. 2011 March 16; 133(10): 3570–3581. doi:10.1021/ja109904u. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript