The Statistical Assessment of Modeling of Proteins and Ligands (SAMPL) series of blind predictive challenges this year focused on  'drugs of abuse' such as morphine, hydromorphone, cocain and the like binding to the synthetic cucurbit[8]uril receptor.<br/>These host-guest complexes are characterized by weak intermolecular interactions such as hydrogen bonding, van der Waals and electrostatic interactions. Accurate calculations of Gibbs free energies of binding pose a challenge to current forcefield-based and quantum chemical methods. In particular, sufficient sampling of conformational possibilities of flexible ligand molecules is difficult to achieve.<br/>We here present results from an automated workflow which consists of a meta-dynamic QM sampling of the conformational energy landscape, an identification and generation of a representative ensemble of conformers and rotameters and a ranking of receptor-ligand complexes according to their Gibbs free energies of binding. The semi-empirical GFN2-xTB method gives calculated Gibbs free energies of binding within a few kcal/mol of the experimental results. This approach is reliable and computationally feasible to obtain macromolecular receptor-ligand free energies of binding for weakly interactiong non-covalent complexes.

QM calculated free energies of binding of macromolecular ligand-receptor complexes

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.