Molecular dynamics study of amyloid formation of two Abl-SH3 domain peptides.

Molecular dynamics (MD) simulations were carried out for two-strand and ten-strand beta-sheets constructed from two peptides corresponding to the diverging turn of two homologous Abl-SH3 domains, DLSFMKGE (MK; from Drosophila) and DLSFKKGE (KK; from man), in explicit water at the temperatures of 30, 170/190 and 300 K. It was found that the 2 x MK beta-sheet is more stable than the 2 x KK beta-sheet, and that the 10 x MK beta-sheet is more stable than the 10 x KK beta-sheet; this suggests that the MK systems are fibril-creating and the KK systems are not. These results might explain why most SH3 domains possess two conserved basic residues at the diverging turn, which may act as gatekeepers in order to avoid aggregation.     

Spatial Structure of Dihydropyridines and Similarity of Dihydropyridines with some Amino Acids

Semi-empirical (PM3) and ab-initio (PSGVB) calculations were carried out for 1,4-dihydropyridine (DHP) and various of its derivatives and also for related amino acids, in order to understand the conformational changes brought about by the substituents and the peptidomimetic properties of the DPH derivatives, in terms of the similarity of their spatial structure to those of related peptides. The results allow us to derive some conformational rules in terms of the nature and position of the susbtituents on the DHP ring and also to conclude that the DHP derivatives exhibit conformational similarities to the related amino acids, which explains their binding to common receptors. This revised version was published online in June 2006 with corrections to the Cover Date.     

Towards gelsolin amyloid formation

Amyloid diseases result from protein misfolding and aggregation into fibrils. Some features of gelsolin amyloidogenic fragments comprised of residues 173-243 (G173-243) and residues 173-202 (G173-202) were investigated by the method of molecular dynamics (MD). The alpha-helical structure of G173-243 present in the whole protein unwinds during the course of MD simulation of the fragment G173-243, suggesting that the G173-243 structure is not stable and could unfold before becoming involved in gelsolin amyloid fibril formation. Twelve fragments of G173-202 were used to build a possible beta-fibril. During the course of the simulation, G173-202 fragments formed hydrogen bonds and tended to turn by an angle of 10 degrees -20 degrees towards each other.