Molecular dynamics simulation of halogen bonding mimics experimental data for cathepsin L inhibition

Abstract

A MD simulation protocol was developed to model halogen bonding in protein–ligand complexes by inclusion of a charged extra point to represent the anisotropic distribution of charge on the halogen atom. This protocol was then used to simulate the interactions of cathepsin L with a series of halogenated and non-halogenated inhibitors. Our results show that chloro, bromo and iodo derivatives have progressively narrower distributions of calculated geometries, which reflects the order of affinity I[Br[Cl, in agreement with the IC50 values. Graphs for the Cl, Br and I analogs show stable interactions between the halogen atom and the Gly61 carbonyl oxygen of the enzyme. The halogen-oxygen distance is close to or less than the sum of the van der Waals radii; the C–X O angle is about 170 ; and the X O=C angle approaches 120 , as expected for halogen bond formation. In the case of the iodo-substituted analogs, these effects are enhanced by introduction of a fluorine atom on the inhibitors’ halogenbonding phenyl ring, indicating that the electron withdrawing group enlarges the r-hole, resulting in improved halogen bonding properties.