Halogen Bonding: An Underestimated Player in Membrane–Ligand Interactions

Abstract

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 modulate protein-ligand interactions, but are also found in engineered protein or nucleic acid systems. In this work, we report direct evidence for the existence of XBs in the context of biological membrane systems thus expanding the scope of application of these interactions. Indeed, our molecular dynamics simulations show the presence of favorable interactions between halobenzene derivatives and both phosphate or ester oxygen acceptors from model phospholipid bilayers, thus supporting the existence of XB mediated phospholipid-halogen recognition phenomena influencing the membrane insertion profile of the ligands and their orientational preferences. This represents a relevant interaction, previously overlooked, eventually determining the pharmacological or toxicological activity of halogenated compounds and hence with potential implications in drug discovery and development, a place where such species account for a significant part of the chemical space. We also provide insights into a potential role for XBs in water-to membrane insertion of halogenated ligands as XBs are systematically observed during this process. Therefore, our data strongly suggests that, as the ubiquitous hydrogen bond, XBs should be accounted for in the development of membrane partition models. File list (2) download file view on ChemRxiv 2021-XB-membranes-Nunes-Vicosa-Costa-ver3.pdf (5.43 MiB) download file view on ChemRxiv 2021-XB-membranes-Nunes-Vicosa-Costa-ver3-SI.pdf (10.30 MiB)

Martini 3 Coarse‐Grained Force Field: Small Molecules

“…[ 24 ] Moreover, such labels could be used to capture halogen‐bonding capabilities of X‐beads, as such interactions have been recently shown to be important in, for example, membrane‐small molecule interactions. [ 30 ] The “e” label is also applied to, for example, the central bead describing naphthalene—which is hence a TC5e bead, see Table 1—being that an electron‐rich region of the molecule.…”

Martini 3 Coarse-Grained Force Field: Small Molecules

“…24 Moreover, such labels could be used to capture halogen-bonding capabilities of X-beads, as such interactions have been recently shown to be important in, for example, membrane-small molecule interactions. 29 The 'e' label is also applied to, for example, the central bead describing naphthalene-which is hence a TC5e bead, see Table 1-being that an electron-rich region of the molecule.…”

Investigating the Permeation Mechanism of Typical Phthalic Acid Esters (PAEs) and Membrane Response Using Molecular Dynamics Simulations

“…Molecular dynamic (MD) simulation is one of the best strategies to explore the penetration mechanism of PAEs across membrane at an atomic level, providing insights into structural information and interaction details that cannot be obtained from classical wet experiments. From previous studies, MD simulation performs well in predicting the permeability of drug-like molecules [23], analyzing the key influencing factors, and addressing questions about how the membranes respond to small molecules' interference and alleviate their harm [24][25][26]. In the present research, we simulated the transmembrane behaviors of three typical PAEs molecules (DMP, DBP, and DEHP, Figure 1b-d) via conventional MD simulations, and identified how PAEs were inserted into POPC (1-Palmitoyl-2-oleoyl-snglycero-3-phosphorylcholine) lipid bilayers and how the intra-membrane aggregation of PAEs molecules affected the properties of the membrane.…”