title: Ligand Affinities Estimated by Quantum Chemical Calculations.
abstract: We present quantum chemical estimates of ligand-binding affinities performed, for the first time, at a level of theory for which there is a hope that dispersion and polarization effects are properly accounted for (MP2/cc-pVTZ) and at the same time effects of solvation, entropy, and sampling are included. We have studied the binding of seven biotin analogues to the avidin tetramer. The calculations have been performed by the recently developed PMISP approach (polarizable multipole interactions with supermolecular pairs), which treats electrostatic interactions by multipoles up to quadrupoles, induction by anisotropic polarizabilities, and nonclassical interactions (dispersion, exchange repulsion, etc.) by explicit quantum chemical calculations, using a fragmentation approach, except for long-range interactions that are treated by standard molecular-mechanics Lennard-Jones terms. In order to include effects of sampling, 10 snapshots from a molecular dynamics simulation are studied for each biotin analogue. Solvation energies are estimated by the polarized continuum model (PCM), coupled to the multipole-polarizability model. Entropy effects are estimated from vibrational frequencies, calculated at the molecular mechanics level. We encounter several problems, not previously discussed, illustrating that we are first to apply such a method. For example, the PCM model is, in the present implementation, questionable for large molecules, owing to the use of a surface definition that gives numerous small cavities in a protein.
authors.affiliation: Department of Theoretical Chemistry, Lund University, Chemical Centre, P.O. Box 124, 221 00 Lund, Sweden, and Department of Physics and Chemistry, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark.
authors.forename: Pär
authors.initials: P
authors.lastname: Söderhjelm
authors.affiliation: Department of Theoretical Chemistry, Lund University, Chemical Centre, P.O. Box 124, 221 00 Lund, Sweden, and Department of Physics and Chemistry, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Kongsted
authors.affiliation: Department of Theoretical Chemistry, Lund University, Chemical Centre, P.O. Box 124, 221 00 Lund, Sweden, and Department of Physics and Chemistry, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark.
authors.forename: Ulf
authors.initials: U
authors.lastname: Ryde