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.
keywords
MOLECULAR-DYNAMICS SIMULATIONS; RECEPTOR CHEMISTRY HIGHLIGHTS; PI SLIDES; MEDICINAL CHEMISTRY; TAMBJAMINE-ANALOGS; CHLORIDE TRANSPORT; LIPID-BILAYERS; FORCE-FIELD; BIS-UREAS; RECOGNITION
subject category
Chemistry; Physics
authors
Marques, I; Costa, PMR; Miranda, MQ; Busschaert, N; Howe, ENW; Clarke, HJ; Haynes, CJE; Kirby, IL; Rodilla, AM; Perez-Tomas, R; Gale, PA; Felix, V
our authors
Igor Oliveira Marques
Junior Researcher
Margarida Sofia Quintanilha Miranda
PhD Student
Pedro Costa
Research Fellowship
Vítor Félix
Associate Professor with AggregationProjects
CICECO - Aveiro Institute of Materials (UID/CTM/50011/2013)
Solucao de Engenharia Microestrutural para Aumentar o Transporte Ionico Interfacial (MERIT)
acknowledgements
The theoretical studies were supported by projects P2020-PTDC/QEQ-SUP/4283/2014 and CICECO - Aveiro Institute of Materials (UID/CTM/50011/2013), financed by National Funds through the FCT/MEC and co-financed by QREN-FEDER through COMPETE under the PT2020 Partnership Agreement. I. M. acknowledges FCT for PhD scholarship SFRH/BD/87520/2012. P. A. G. acknowledges the EPSRC for postdoctoral fellowships (EP/J009687/1 to N. B. and E. N. W. H.) and the Royal Society and theWolfson Foundation for a Research Merit Award. P. A. G. also thanks for the University of Sydney for postdoctoral funding (E. N. W. H.) and the ARC for funding (DP170100118, DP180100612 and LE180100050). The in vitro studies were supported by grants from the Spanish government and the EU (FIS PI13/00089) and La Marato de TV3 Foundation (20132730).