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 beta-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 beta-sheet structure, which is formed by packing the RT-loops from different proteins. Our simulations are consistent with a possible generic amyloidogenesis scenario.
Ding
Feng
F
Center for Polymer Studies, Department of Physics, Boston University, Boston, MA 02215, USA.
Dokholyan
Nikolay V
NV
Buldyrev
Sergey V
SV
Stanley
H Eugene
HE
Shakhnovich
Eugene I
EI
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D000686:Amyloidosis / Q000209:etiology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D019281:Dimerization; D006860:Hydrogen Bonding; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry; D016415:Sequence Alignment; D013696:Temperature; D018909:src Homology Domains
D000682:Amyloid; D010446:Peptide Fragments; D021122:Protein Subunits