With the popularity of halogen bonding on the rise, particularly in life sciences and drug discovery, there is an increasing demand for computational tools recognizing and evaluating this interaction. Several MM parameterizations and QM/MM methods have been recently developed to facilitate the study of these interactions. In addition to these efforts, creation of a scoring function will enable the rapid assessment of halogen bond geometries and help to derive their interaction qualities.Recently, we have used a myriad of QM model calculations on the MP2/TZVPP-level of theory to systematically map the relationship between strength and geometry of halogen bonds to different interaction partners (carbonyl backbone, sulfur contacts, nitrogen contacts, carboxylates, p-systems, �). Database mining of the PDB has led to various analyses about the existing number of halogen bonds and their structural attributes. However, it is even more interesting to evaluate the potential of protein-ligand complexes for the molecular design of additional halogen bonds based on the existing binding mode. We have created a tool to extract all possible undecorated, aromatic positions in ligands that, when decorated by chlorine, bromine, or iodine, can form favorable interactions with a backbone carbonyl, while not showing significant clashes with the binding site or the other moieties of the ligand. For this task, we have created a scoring function representing > 105 MP2 single point energies to encode the relationship between geometry and interaction quality. Applying this scoring function, about 1000 examples could be extracted from the PDB showing both useful halogen bonds and low clash scores upon introduction of an iodine at a (hetero)aromatic scaffold. We have validated these results, demonstrating that the predicted scores still represent the QM-based adduct formation energies (R2= 0.87). I will highlight, how we can extend this study toward a generally applicable scoring function.

Towards a QM-based scoring function for the recognition and assessment of halogen bonds

248th National Meeting (2014)

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