Multiple β-sheet molecular dynamics of amyloid formation from two ABl-SH3 domain peptides

Molecular dynamics simulations in explicit water were carried out for two stacks, each composed of six 10-strand antiparallel beta-sheets for two peptides corresponding to the diverging turn of two homologous Abl-SH3 domains. The first system, referred to as 10x6xMK contained the DLSFMKGE sequence from the Drosophila, while the second one, referred to as 10x6xKK, contained the human DLSFKKGE sequence. It was found that the 10x6xMK beta-sheet stack is stable, but the 10x6xKK beta-sheet stack is not. The stability of the 10x6xMK beta-sheet stack results from the hydrophobic interactions of the methionine and phenylalanine residues and the leucine residues of the neighboring sheets. The Met, Phe, and Leu hydrophobic units make a hydrophobic core for the stack of beta-sheets. During the MD run, the Met, Phe, and Leu residues of the neighboring beta-sheets acted as a conformational switch moving the beta-sheets so that the Phe residue interacted with the Met residue from the neighboring beta-sheet. Replacement of Met by Lys destroys the hydrophobic core, which is the stability factor of the beta-sheet stack. For the 10x6xKK system, individual beta-sheets were preserved during simulations, but the interactions between the beta-sheets were lost. The calculations of a six beta-sheet stack confirm the conclusion drawn from our earlier studies of single beta-sheet systems that the beta-sheets must form stacks to be stabilized. These results suggest that the two conserved basic residues at the diverging turn of SH3 domains could act as gatekeepers to avoid aggregation. (C) 2012 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 98: 557566, 2012.