Halogen Bonding: An Underestimated Player in Membrane–Ligand Interactions

Halogen bonds (XBs) are noncovalent interactions where halogen atoms act as electrophilic species interacting with Lewis bases. These relevant in biochemical systems being increasingly explored drug discovery, mainly to modulate protein–ligand interactions, but also found engineered protein or nucleic acid systems. In this work, we report direct evidence for the existence of XBs context biological membrane systems, thus expanding scope application these interactions. Indeed, our molecular dynamics simulations show presence favorable between halobenzene derivatives and both phosphate ester oxygen acceptors from a model phospholipid bilayer, supporting XB-mediated phospholipid–halogen recognition phenomena influencing insertion profile ligands their orientational preferences. This represents interaction, previously overlooked, eventually determining pharmacological toxicological activity halogenated compounds hence potential implications discovery development, place such account significant part chemical space. We provide insights into role water-to-membrane systematically observed during process. Therefore, data strongly suggest that, ubiquitous hydrogen bond, should be accounted development partition models.