Tris–thiourea tripodal-based molecules as chloride transmembrane transporters: insights from molecular dynamics simulations

Abstract

The interaction of six tripodal synthetic chloride transmembrane transporters with a POPC bilayer was investigated by means of molecular dynamics simulations using the general Amber force field (GAFF) for the transporters and the LIPID11 force field for phospholipids. These transporters are structurally simple molecules, based on the tris(2-aminoethyl)amine scaffold, containing three thiourea binding units coupled with three n-butyl (1), phenyl (2), fluorophenyl (3), pentafluorophenyl (4), trifluoromethylphenyl (5), or bis(trifluoromethyl)phenyl (6) substituents. The passive diffusion of 1-6⊃ Cl(-) was evaluated with the complexes initially positioned either in the water phase or inside the bilayer. In the first scenario the chloride is released in the water solution before the synthetic molecules achieve the water-lipid interface and permeate the membrane. In the latter one, only when the chloride complex reaches the interface is the anion released to the water phase, with the transporter losing the initial ggg tripodal shape. Independently of the transporter used in the membrane system, the bilayer structure is preserved and the synthetic molecules interact with the POPC molecules at the phosphate headgroup level, via N-H···O hydrogen bonds. Overall, the molecular dynamics simulations' results indicate that the small tripodal molecules in this series have a low impact on the bilayer and are able to diffuse with chloride inside the lipid environment. Indeed, these are essential conditions for these molecules to promote the transmembrane transport as anion carriers, in agreement with experimental efflux data.

Understanding Interfacial Mechanics and Mechanisms of Exfoliation and Stabilization of Graphene Using Urea/Glycerol Solvents

“…The topology profiles of graphene, urea, and glycerol were generated using the ACPYPE scripts with the generalized AMBER force field (GAFF) parameters . Similar to other force fields (i.e., CHARMM, OPLS, and GROMOS), the GAFF is also able to successfully reproduce structural and dynamical properties of organic molecules of interest where hydrogen bonds are involved . The carbon atoms in graphene sheets were modeled as uncharged Lennard–Jones (LJ) particles.…”

Halogen Bonding: An Underestimated Player in Membrane–drug Interactions

“…To study the potential role of HaBs in membrane-drug recognition phenomena, the cell membrane was modeled as a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer. [55][56][57] A series of iodobenzene derivatives (Figure 1c), capable of establishing HaBs, were chosen as probes. Iodopentafluorobenzene (5f ibz), exhibiting a considerable σ-hole corresponding to a local maximum on the electrostatic potential (V max ) of 32.3 kcal mol −1 (B3LYP/6-311G(d,p)) and a HaB-mediated transmembrane anion transport activity (EC 50 ) of 260 µM 49 was selected as a strong HaB donor probe together with iodobenzene (ibz) which is a considerably weaker HaB donor (V max = 16.9 kcal mol −1 ) and exhibits much negligible transmembrane anion transport activity (EC 50 > 2 mM).…”

“…53,54 As for anion transporters that are known to interact directly with lipid membranes by establishing HBs with several nucleophilic sites from the phospholipid headgroups, i.e. oxygen atoms, [55][56][57] halogen-bonding anion transporters, or any other HaB donor molecule, may eventually engage in an interaction with those sites as well (Figure 1a). Those sites, divided into two dynamic outer membrane regions with the phosphate oxygen (PO) acceptors more exposed to water and the ester oxygen (CO) acceptors located closer to the membrane Figure 1: (a) Representation of a phosphatidylcholine (PC) molecule highlighting the different lipid HaB-(or HB-) acceptor sites (X = Cl, Br, I or OH; R = substituent); (b) PO-(green) and CO-type (blue) acceptor layers in a representative POPC bilayer; (c) Iodobenzene derivatives studied in this work, their molecular electrostatic potentials (ESPs) mapped on the 0.001 au contour of the electron density (values in kcal mol −1 ), and V max at I (and OH for iphen) computed at the B3LYP/6-311G(d,p) level.…”

Full elucidation of the transmembrane anion transport mechanism of squaramides using in silico investigations

“…Furthermore, a proof of concept study with a cationic calix [4]arene in a DOPC membrane allowed us to observe the passive transport of chloride assisted by a synthetic anion carrier for the first time. 72 We have extended the MD investigations with membrane models to the study of the interaction of ortho-phenylene-diamine-based bisurea molecules 30 and trenbased tris-thiourea compounds 73 with POPC bilayers. More recently, MD studies on a series of dithioureidodecalin transporters with different alkyl chains lengths, allowed us to establish a relation between their transport abilities and their tilting and tumbling within the bilayer, which are slowed down by the increasing length of the alkyl chains via van der Waals interactions with phospholipid tails.…”