title: Molecular dynamics simulation of the SH3 domain aggregation suggests a generic amyloidogenesis mechanism.
abstract: 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.
authors.affiliation: Center for Polymer Studies, Department of Physics, Boston University, Boston, MA 02215, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Ding
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Dokholyan
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Buldyrev
authors.forename: H Eugene
authors.initials: HE
authors.lastname: Stanley
authors.forename: Eugene I
authors.initials: EI
authors.lastname: Shakhnovich
mesh_terms: 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
chemical_list: D000682:Amyloid; D010446:Peptide Fragments; D021122:Protein Subunits