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

Abstract

A comprehensive experimental and theoretical investigation of the transmembrane chloride transport promoted by four series of squaramide derivatives, with different degrees of fluorination, number of convergent N-H binding units and conformational shapes, is reported. The experimental chloride binding and transport abilities of these small synthetic molecules in liposomes were rationalised with quantum descriptors and molecular dynamics simulations in POPC bilayers. The tripodal tren-based compounds, with three squaramide binding motifs, have high chloride affinity, isolating the anion from water molecules within the membrane model and preventing its release to the aqueous phase, in agreement with the absence of experimental transport activity. In contrast, the symmetrical mono-squaramides, with moderate chloride binding affinity, are able to bind and release chloride either in the aqueous phase or at the membrane interface level, in line with experimentally observed high transport activity. The PMF profiles associated with the diffusion of these free transporters and their chloride complexes across phospholipid bilayers show that the assisted chloride translocation is thermodynamically favoured.

Redox-controlled chalcogen and pnictogen bonding: the case of a sulfonium/stibonium dication as a preanionophore for chloride anion transport

“…Such arguments have been previously advanced to rationalize the poor performance of organic, hydrogen-bond donor transporters. 52,53 Another factor that could explain the low transport activity of [3] 2+ and [4] 2+ is their possibly excessive chloride anion affinity, which may impede dynamic capture and release of the anion. 50,54,55 A similar argument could be used to explain the better performance of [2] + when compared to [1] + .…”

Development of a Library of Thiophene‐Based Drug‐Like Lego Molecules: Evaluation of Their Anion Binding, Transport Properties, and Cytotoxicity

“…The high affinity of our smallm olecules for these hydrogen-bond acceptors( see below)m ight play an important role in their ability to promote transmembrane chloride transport, given that the anion uptake necessarily occurs at the water/lipid interfacel evel, as we have previously demonstrated. [27,28] The counting of NÀH···Cl À hydrogen bonds throughout the MD runs carriedo ut in scenario L indicates that 3, 4, 8, 9, 14, 16,a nd 17 typically release the anion within the first 50 ns of simulation. In contrast, in one of the initial MDr uns with 15, dissociation of the complex occurs almost at the end of the MD simulation (ca.…”

Direct Monitoring of Bicarbonate Transport by Emission Spectroscopy

“…8,9 While the development of HCO3 − transporters was defined as "an interesting target with potential utility" by A. P. Davis, Sheppard, and Smith in 2006, 10 J. T. Davis, Gale, Quesada and co-workers reported in 2009 that a series of isophthalamides and the natural compound prodigiosin can act as Cl − /HCO3 − exchangers. 11 Since then, many different anion transporters have been shown to transport HCO3 − , of which the vast majority have urea, 12,13,14 thiourea, 15,16,17 squaramide, 18,19 amide, 11,20,21 or pyrrolic N-H groups 22,23 as H-bond donors. Phenyl rings with electron withdrawing substituents are often connected to these functional groups to increase the acidity of the N-H groups and improve both the affinity for anions and the rates of transport.…”

“…Phenyl rings with electron withdrawing substituents are often connected to these functional groups to increase the acidity of the N-H groups and improve both the affinity for anions and the rates of transport. [12][13][14][17][18][19] A series of compounds that was shown to function efficiently as Cl − /HCO 3 − exchanging anionophores, but without employing N-H based H-bond donors, are the fluorinated bambus [6]urils. 24 These macrocyclic receptors have an electron deficient cavity formed by twelve (polarised) methine C-H groups, which leads to exceptionally high affinity constants in the range of 10 7 -10 11 M -1 in acetonitrile for HCO3 − , Cl − , and NO3 − , despite the absence of acidic protons.…”

“…In most cases, a chloride selective electrode has been employed to study the efflux of Cl − from liposomes that were dispersed in a medium containing HCO3 − . 37,11,[13][14][15][16][17][18][19][21][22][23]33 The transport of Cl − out of the liposomes proceeds only if another anion is transported in the opposite direction, to balance the charge by an antiport process. From the observed efflux of Cl − it is then concluded that an influx of HCO3 − has occurred.…”