Molecular dynamics simulation of the SH3 domain aggregation suggests a generic amyloidogenesis mechanism

We use molecular dynamics simulation to study the aggregation of Src SH3 domain proteins. For the case of two proteins, we observe two possible aggregation conformations: the closed form dimer and the open aggregation state. The closed dimer is formed by "domain swapping" - the two proteins exchange their RT-loops. All the hydrophobic residues are buried inside the dimer so proteins cannot further aggregate into elongated amyloid fibrils. We find that the open structure - stabilized by backbone hydrogen bond interactions - packs the RT-loops together by swapping the two strands of the RT-loop. The packed RT-loops form a β-sheet structure and expose the backbone to promote further aggregation. We also simulate more than two proteins, and find that the aggregate adopts a fibrillar double β-sheet structure, which is formed by packing the RT-loops from different proteins. Our simulations are consistent with a possible generic amyloidogenesis scenario.