Transmembrane transport of chloride by Squaramides : in silico study

• Autor(a) principal: Colaço, Ana Rita Freitas
• Data de Publicação: 2013
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/12505
• topic: Biomedicina; Fibrose quística; Dinâmica molecular; Cloretos

The anion transport across cellular membranes is essential to the cell functioning and its regulation depends on transmembrane channels. The malfunction of ion channels leads to channelopathies. In particularly, the impairment of chloride ion channels is associated with cystic fibrosis. These diseases have motivated the supramolecular chemists for the development of new chloride synthetic transporters with potential use in channel replacement therapies. In this context, this thesis reports an in silico study performed to evaluate the ability of five squaramides to assist the chloride transport across a POPC bilayer. Indeed, earlier experimental studies have shown that these small molecules were able to mediate the chloride efflux across POPC vesicles more efficiently than their analogous thioureas and ureas, as mobile-carriers using an anion-exchange mechanism. This theoretical investigation was carried out by a combination of quantum calculations and Molecular Dynamics simulations in a POPC membrane model. The MD simulations were preceded by the development of specific bond term parameters for the squaramide moiety using the crystal data from an extensive series of squaramides. The remaining parts of these molecules were described with GAFF default parameters. The phospholipids were described with parameters taken from LIPID11. The passive diffusion of chloride complexes was investigated by placing each receptor in two different starting positions: in the water slab and in the bilayer core of the POPC membrane model. In both cases the receptor moved towards the water/lipid interface and accommodated themselves below the lipid head groups. In the first case, the chloride release occurred in the water slab before the receptor reaches the water/lipid interface. By contrast, in the second case the chloride is released concomitantly with the receptor approach to the interface. The squaramides interact with phospholipid head groups mainly via N-H···O hydrogen bonds as analyzed along the thesis.