Prediction of the absolute aggregation rates of amyloidogenic polypeptide chains.
Protein aggregation is associated with a variety of pathological conditions, including Alzheimer's and Creutzfeldt-Jakob diseases and type II diabetes. Such degenerative disorders result from the conversion of the normal soluble state of specific proteins into aggregated states that can ultimately form the characteristic amyloid fibrils found in diseased tissue. Under appropriate conditions it appears that many, perhaps all, proteins can be converted in vitro into amyloid fibrils. The aggregation propensities of different polypeptide chains have, however, been observed to vary substantially. Here, we describe an approach that uses the knowledge of the amino acid sequence and of the experimental conditions to reproduce, with a correlation coefficient of 0.92 and over five orders of magnitude, the in vitro aggregation rates of a wide range of unstructured peptides and proteins. These results indicate that the formation of protein aggregates can be rationalised to a considerable extent in terms of simple physico-chemical parameters that describe the properties of polypeptide chains and their environment.
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Kateri F
KF
DuBay
Amol P
AP
Pawar
Fabrizio
F
Chiti
Jesús
J
Zurdo
Christopher M
CM
Dobson
Michele
M
Vendruscolo
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D008962:Models, Theoretical; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012044:Regression Analysis; D012996:Solutions / Q000737:chemistry
D000682:Amyloid; D010455:Peptides; D012996:Solutions