We report a method that was recently developed in our group, Quantum-Mechanical Mining Minima (QM/M2), for accurately computing the binding affinities of host-guest systems. The semi-empirical quantum mechanical model, PM6-DH+, was used for computing the energy, configurational entropy, and free-energies. After correction for a systematic error, which appears to derive from the treatment of polar solvation, the computed absolute binding affinities agree well with experimental measurements, with a mean error of 1.6 kcal/mol and a correlation coefficient of 0.91. These calculations also delineate the contributions of various energy components, including solute energy, configurational entropy, and solvation free energy, to the binding free energies of these host�guest complexes. Comparison with our previous calculations, which used empirical force fields, point to significant differences in both the energetic and entropic components of the binding free energy. The present study demonstrates a successful combination of a quantum mechanical Hamiltonian with the M2 affinity method.

Computing binding affinities of supramolecular host-guest systems

245th National Meeting (2013)

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