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Comment on “HYDROPHOBE Challenge: A Joint Experimental and Computational Study on the Host -Guest Binding of Hydrocarbons to Cucurbiturils” Hans-Jorg Schneider J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.8b00297 • Publication Date (Web): 22 Feb 2018 Downloaded from http://pubs.acs.org on March 3, 2018
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Comment on “HYDROPHOBE Challenge: A Joint Experimental and Computational Study on the Host−Guest Binding of Hydrocarbons to Cucurbiturils”
Hans-Jörg Schneider, FR Organische Chemie, Universität des Saarlandes, D 66041 Saarbrücken, Germany ,
[email protected] A recent publication by Assaf et al on the complexation of hydrocarbons with cucurbit[7]uril 1 sheds light on problems with the prediction of host-guest complexes with computational methods. Several claims and shortcomings of the paper deserve an additional comment. Other than in many related papers the complexation energies were calculated prior to knowledge of experimental data, thus presenting an unbiased blind test for the computational accuracy. Also, other than in most of earlier publications2 the experimental affinities were determined in absence of metal ions which are known to affect the affinities. As computational methods, two explicit-solvent molecular dynamics (MD) methods, using also molecular mechanics,3,4 and three dispersion-corrected quantum-chemical DFT (DCMF, QM) methods,5 were used. It was noted that the QM-derived values require a reference-state adjustment. Nevertheless, the correlations between calculated and experimental free binding energies were considered to be good, although the coefficients ranged between R2 values of 0.84 and 0.75. More important, the slope of correlation lines were mostly way off the expected value of 1.0, indicating generally much higher affinities than experimentally observed (Table 1). Particularly large deviations, up to 100%, were observed with the MD calculations, which at the same time showed better correlations. For n-heptane large deviations were obtained with both QM and MD although this complex was experimentally completely in line with other n-alkanes (Figure S1). Disturbingly, one method which was performing better for a particular complex often showed less agreement with another complex (see Table 1, bold and italics values).
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Table 1. Selected Binding Free Energies (∆G, kcal mol–1) from ref. 1a experimental
calculated ∆G
∆G
QM1 QM2 QM3 MD1 MD2
propane
–5.15
–2.14 –4.78 –5.92 –8.34 –8.60
n-butane
–7.14
–3.74 –7.00 –7.97 –12.18 –12.60
n-pentane
–7.75
–5.11 –8.14 –8.14 –14.12 –14.42
n-hexane
–8.43
–5.98 –6.48 –6.98 –15.81 –15.68
n-heptane
-8.94
-6.85 -4.94 -5.21 -12.44 -12.54
propene
-4.19
-0.72 -3.10 -3.45 -4.92 -6.16
–8.43
–9.98 –13.25 –13.41 –17.32 –18.03
–5.77
–7.64 –7.93 –9.53 –9.75 –13.77
- cyclohexane benzene
a) values with best agreement with experiments are in bold and italics The basis of the paper were hydrocarbons as guests, which in contrast to earlier investigations with polar or ionic guest molecules,2 are computationally less demanding; nevertheless realistic predictions of such host–guest affinities present obviously still a challenge. It has been noted that all semiempirical methods like DCMF should in absence of experimental benchmarks checked with data from correlated wave function based approaches, or e.g. quantum Monte Carlo methods; these were declared to be the defacto standard in the field of theoretical noncovalent interaction calculations.5,6 Noticeably, the corresponding data set predicts e.g. for the benzene dimer (∆H = -2.76 kcal/mol) gas phase stabilities to be smaller than that for the benzene-cyclopentane dimer ( -3.53 kcal/mol), or even the cyclopentane-cyclopentane dimer (2.98 kcal/mol).6,7 It would be more than timely to test these unexpected values with experimental measurements in the gas phase. Present-day computations of non-covalent interactions can encompass a large variety of intermolecular associations, and are applied to almost countless complexes. Widely used QSPR (quantitative structure-property relations) approaches, based on trainings sets of experimentally known complexes and molecular similarity-based screening methods serve the same purpose. Typically, many descriptors are necessary for a sufficiently accurate prediction, e.g. seven descriptors for cyclodextrin complexes.8 All these approaches finally aim at the understanding of the different non-covalent interactions, and their use for the design of drugs, or of new chemical systems and materials for many applications. Alternative approaches, based not on the indiscriminate use of all available data but on the use of rationally pre-selected complexes may be better suited to identify and to quantify the relevant non-covalent forces. Empirical linear correlations between free energy increments ∆∆G and observed total binding energies prove their additivity, and allow to characterize physical parameters ACS Paragon Plus Environment
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for the energy contributions, which then can be used to predict unknown complexes.9,10,11 Unfortunately, no conclusions are drawn in the JPC B paper by Assaf et al1 as to which are the dominant physical forces in cucurbituril complexes. Correlations from the literature such as those described in the Supplementary Material show that e.g. electrostatics can predict stabilities of crown and cryptand, of hydrogen bonded, of ion pairs and of many other complexes; Hammett-type correlations are particularly helpful for such predictions.
Linear correlations with single empirical parameters can, however, also be misleading. Thus, the cucurbituril complexes discussed in the publication of Assaf et al do show a surprisingly linear correlation between ∆G and the polarizability of the ligands ( see Figure S2, Supplementary Information). However, experimental evidence speaks clearly for an extremely weak polarizability inside cucurbiturils,12,13 and hydrocarbons have also notoriously polarizability values. These increase with the molecular size, which might be the major factor in the observed correlation. All experimental evidence speaks in fact for the release of intracavity high energy water as driving force for complexation with these cucurbiturils,14,15 a contribution which would require instead of COSMO continuum models1 explicit calculations for discrete water molecules, and may be a major cause for the discrepancies in the publication by Assaf et al.1 Supporting Information Examples of empirical free energy correlations for supramolecular complexes, for example as function of polar substituent constants, acidity or basicity values, or electrostatics. This material is available free of charge via the Internet at http://pubs.acs.org.
1
Assaf, K. I. ; Florea, M.; Antony, J.; Henriksen, N.; Hansen, A.; Yin, J.; Sure, R. Klapstein, D.;
Gilson, M.; Grimme, S.; Nau, W.M. HYDROPHOBE Challenge: A Joint Experimental and Computational Study on the Host−Guest Binding of Hydrocarbons to Cucurbiturils, Allowing Explicit Evaluation of Guest Hydration Free-Energy Contributions J. Phys. Chem. B 2017, 121, 11144−11162. 2
Guo, D.S.; Uzunova, V.D.¸ Assaf, K.I. ; Lazar, A.I.; Liu, Y., Nau, W.M. Inclusion of neutral guests
by water-soluble macrocyclic hosts—a comparative thermodynamic investigation with cyclodextrins, calixarenes and cucurbiturils. Supramol. Chem. 2016, 28, 384–395; and ref. 51, 52, 61 to 65 in ref 1. 3
Mobley, D. L.; Gilson, M. K. Predicting Binding Free Energies: Frontiers and Benchmarks Annual
Rev. Biophysics 2017, 46 , 531-558. 4
Henriksen, N. M.; Fenley, A. T.; Gilson, M. K. Computational Calorimetry: High-Precision
Calculation of Host-Guest Binding Thermodynamics. J. Chem. Theory Comput. 2015, 11, 4377−4394.
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Grimme, S.; Hansen, A.; Brandenburg, J. G.; Bannwarth, C. Dispersion-Corrected Mean-Field
Electronic Structure Methods Chem. Rev. 2016, 116 , 5105-5154. 6
Rezac, J.; Hobza, P. Benchmark Calculations of Interaction Energies in Noncovalent Complexes and
Their Applications Chem. Rev. 2016, 116, 5038-5071. 7
Marshall, M. S.; Burns, L. A.; Sherrill, C. D. Basis set convergence of the coupled-cluster correction
J. Chem. Phys. 2011, 135, 194102. 8
Steffen, A.; Karasz, M.; Thiele, C.; Lengauer, T. ; Kämper, A.; Wenz, G.; Apostolakis, J. Combined
similarity and QSPR virtual screening for guest molecules of ß-cyclodextrin New J. Chem., 2007,31, 1941-1949. 9
Schneider, H.-J. Binding Mechanisms in Supramolecular Complexes Angew. Chem. Int. Ed. 2009,
48, 3924-3977. 10
Biedermann, F.; Schneider, H.-J. Experimental Binding Energies in Supramolecular Complexes
Chem. Rev. 2016, 116, 5216– 5300. 11
Hunter, C.A. Quantifying intermolecular interactions: Guidelines for the molecular recognition
toolbox Angew. Chem. Int. Ed. 2004,43 , 5310-5324. 12
Nau, W.M.; Florea, M.; Assaf, I.K. Deep Inside Cucurbiturils Isr. J. Chem. 2011,51, 559 – 577.
13
Assaf, K. I.; Nau, W. M. Cucurbiturils as fluorophilic receptors Supramol. Chem. 2014, 26 , 657-
669. 14
Biedermann, F.; Uzunova, V. D.; Scherman, O. A.; Nau, W. M.;De Simone, A. Release of High-
Energy Water as an Essential Driving Force for the High-Affinity Binding of Cucurbit[n]urils. J. Am. Chem. Soc. 2012, 134, 15318−15323 15
Biedermann, F.; Nau, W. M.; Schneider, H.-J. The Hydrophobic Effect Revisited - Implications
from Studies with Supramolecular Complexes: High-Energy Water as Non-Covalent Driving Force Angew. Chem., Int. Ed. 2014, 53, 11158– 11171.
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