A computational analysis of the first steps of the auto-aggregation of the Gliadin peptide p33”

M.J. AMUNDARAIN; F. ZAMARREñO; M. GIMéNEZ; J.F. VISO; M.G. HERRERA; DODERO V. I; MARCELO COSTABEL

Congreso; XLI Reunión Anual de la Sociedad Argentina de Biofísica; 2012

Coeliac disease is an autoimmune disorder that affects the small intestine and is triggered by the ingestion of food that contains gluten(1,2). It has been found that within the proteins that form gluten, the members of the gliadin family have a 33-mer peptide resistant to digestion. This peptide, LQLQPF(PQPQLPY)3PQPQPF, is proposed to be the main cause of the damage of the epithelial cells of the small intestine(3,4). As a starting point, we studied the monomer through two different approaches, allowing us to gain more information about the structural unit, which will be later applied to the problem of auto-aggregation. We first performed an electrostatic energy calculation using APBS, considering the different force fields available and different pH values. Since we did not find any appreciable difference, we carried on with force field PARSE and physiological pH. After that, we ran a molecular dynamics simulation with GROMACS of about 20ns in explicit water. In a second instance, we analysed the aggregation of two monomers into a dimer following the same procedure. Although the dimer still has a high content of PPII, it can be seen that it adopts different conformations that show â sheet motif. The results found through this work were consistent with the model proposed previously by this group and with experimental facts.(1,2). It has been found that within the proteins that form gluten, the members of the gliadin family have a 33-mer peptide resistant to digestion. This peptide, LQLQPF(PQPQLPY)3PQPQPF, is proposed to be the main cause of the damage of the epithelial cells of the small intestine(3,4). As a starting point, we studied the monomer through two different approaches, allowing us to gain more information about the structural unit, which will be later applied to the problem of auto-aggregation. We first performed an electrostatic energy calculation using APBS, considering the different force fields available and different pH values. Since we did not find any appreciable difference, we carried on with force field PARSE and physiological pH. After that, we ran a molecular dynamics simulation with GROMACS of about 20ns in explicit water. In a second instance, we analysed the aggregation of two monomers into a dimer following the same procedure. Although the dimer still has a high content of PPII, it can be seen that it adopts different conformations that show â sheet motif. The results found through this work were consistent with the model proposed previously by this group and with experimental facts.3PQPQPF, is proposed to be the main cause of the damage of the epithelial cells of the small intestine(3,4). As a starting point, we studied the monomer through two different approaches, allowing us to gain more information about the structural unit, which will be later applied to the problem of auto-aggregation. We first performed an electrostatic energy calculation using APBS, considering the different force fields available and different pH values. Since we did not find any appreciable difference, we carried on with force field PARSE and physiological pH. After that, we ran a molecular dynamics simulation with GROMACS of about 20ns in explicit water. In a second instance, we analysed the aggregation of two monomers into a dimer following the same procedure. Although the dimer still has a high content of PPII, it can be seen that it adopts different conformations that show â sheet motif. The results found through this work were consistent with the model proposed previously by this group and with experimental facts.(3,4). As a starting point, we studied the monomer through two different approaches, allowing us to gain more information about the structural unit, which will be later applied to the problem of auto-aggregation. We first performed an electrostatic energy calculation using APBS, considering the different force fields available and different pH values. Since we did not find any appreciable difference, we carried on with force field PARSE and physiological pH. After that, we ran a molecular dynamics simulation with GROMACS of about 20ns in explicit water. In a second instance, we analysed the aggregation of two monomers into a dimer following the same procedure. Although the dimer still has a high content of PPII, it can be seen that it adopts different conformations that show â sheet motif. The results found through this work were consistent with the model proposed previously by this group and with experimental facts. 1. Shan, L. et. al. Science 297, 2275-2279 (2002). 2. Shan, L. et. al. J. Proteome Res. 4, 1732-1741 (2005). 3. Hadjivassiliou, M., Williamson, C. A. & Woodroofe, N. Trends Immunol. 25, 578-582 (2004). 4. Rubio-Tapia, A. & Murray, J. A. Curr. Opin. Gastroenterol. 26, 116-122 (2010). Acknowledgments: We