Halogen bonding in ligand–receptor systems in the framework of classical force fields

Abstract

Halogen bond is an important non-covalent interaction which is receiving a growing attention in the study of protein-ligand complexes. Many drugs are halogenated molecules and it has been recently shown that many halogenated ligands establish halogen bonds with biomolecules. As the halogen bond nature is due to an anisotropy of the electrostatic potential around halogen atoms, it is not possible to use traditional force fields based on a set of atom-centred charges to study halogen bonds in biomolecules. We show that the introduction of pseudo-atoms on halogens permits us to correctly describe the anisotropy of the electrostatic potential and to perform molecular dynamics simulations on complexes of proteins with halogenated ligands that reproduce experimental values. The results are compared with crystallographic data and with hybrid quantum mechanics/molecular mechanics calculations.

Halogen Bonding in Supramolecular Chemistry

“…120 An equivalent approach using a pseudoatom instead of an extra point of charge was employed with GAFF to perform MD simulations on complexes of proteins with halogenated ligands that reproduce experimental data. 121 The results were also compared with crystallographic data and with hybrid QM−MM calculations.…”

“…Recently, various approaches toward adapting MM methods to account for XB interactions have been reported, such as in the OPLS-AA 126 or AMBER 116,121,328 force fields. Placing a massless pseudoatom, bearing a partial positive charge and possessing no van der Waals energy (a so-called positive extra point (PEP)), has been shown to improve the modeling of XB interaction geometries and interaction energies in the AMBER force field (vide supra).…”

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

“…Computational docking protocols rely on force fields that incorporate a wide array of interactions, but do not include halogen bonds. The first paper to attempt modeling this interaction, introducing the concept of a point charge located on the XÁÁÁY axis, was published in 2011 [15] followed shortly thereafter by another one using a similar approach [16]. Other methodologies are being developed with the expectation that they will be able to provide conclusive evidence for the participation of these interactions in the affinity of specific halogenated molecules with their biological targets.…”

“…In view of the need to predict halogen bonds in the context of drug design, we built on the ''extra point'' or ''explicit r-hole'' concept [15,16], to model the halogen bond in drug-receptor or drug-enzyme interactions, and have applied it successfully to the human cathepsin L inhibitors depicted in Fig. 1.…”

Solvent effect on halogen bonding: The case of the I⋯O interaction

“…In fact, the large number of atoms involved in such systems prohibits the use of QM approaches and makes Quantum Mechanics/Molecular Mechanics (QM/MM) hybrid methods the obliged choice. Suitable modifications of traditional force fields have been however very recently proposed to overcome this problem [22].…”