ABSTRACT
Molecular dynamics simulations in explicit water were carried out for two stacks, each composed of six 10-strand antiparallel ß-sheets for two peptides corresponding to the diverging turn of two homologous Abl-SH3 domains. The first system, referred to as 10×6×MK contained the DLSFMKGE sequence from the Drosophila, while the second one, referred to as 10×6×KK, contained the human DLSFKKGE sequence. It was found that the 10×6×MK ß-sheet stack is stable, but the 10×6×KK ß-sheet stack is not. The stability of the 10×6×MK ß-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 ß-sheets. During the MD run, the Met, Phe, and Leu residues of the neighboring ß-sheets acted as a conformational switch moving the ß-sheets so that the Phe residue interacted with the Met residue from the neighboring ß-sheet. Replacement of Met by Lys destroys the hydrophobic core, which is the stability factor of the ß-sheet stack. For the 10×6×KK system, individual ß-sheets were preserved during simulations, but the interactions between the ß-sheets were lost. The calculations of a six ß-sheet stack confirm the conclusion drawn from our earlier studies of single ß-sheet systems that the ß-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.
