Chemical accuracy for ligand-receptor binding Gibbs energies through multi-level SQM/QM calculations

Abstract

Calculating the Gibbs energies of binding of ligand-receptor systems with a thermochemical accuracy of ± 1 kcal/mol is challenge to computational approaches. After exploration of the conformational space of host, ligand and complexes by semi-empirical GFN2 MD and meta-MD simulations, the systematic refinement through a multi-level improvement of binding modes in terms of electronic energies and solvation is able to give Gibbs energies of binding of drug molecules to CB[8] and β-CD macrocyclic receptor with such an accuracy. The accurate treatment of a small number of structures outperforms system-specific force-matching and alchemical transfer model approaches without an extensive sampling and intergration.