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 interactions are relevant in biochemical systems being increasingly explored in drug discovery, mainly to moduate protein–ligand interactions. In this work, we report evidence for the existence of XB-mediated phospholipid–halogen recognition phenomena as our molecular dynamics simulations support the existence of favorable interactions between halobenzene derivatives and both phosphate or ester oxygen acceptors from model phospholipid bilayers. We also provide insights into the role of XBs in driving the permeation of halogenated small molecules across biological membranes. This represents a relevant molecular mechanism, previously overlooked, eventually determining the pharmacological or toxicological activity of halogenated compounds and hence with implications in drug discovery and development, a place where such species account for a significant part of the chemical space. Our data strongly suggests that, as the ubiquitous hydrogen bond, XBs should be accounted for in the development of membrane permeability models.