Protein Aggregation: Kinetics versus Thermodynamics

In this study, we address the questions of how important
is the
kinetics in protein aggregation, and what are the intrinsic properties
of proteins that cause this behavior. On the basis of our recent quantitative
calculation of the equilibrium phase diagram of natively folded α-helical
and β-sheet forming peptides, we perform molecular dynamics
simulations to demonstrate how the aggregation mechanism and end product
depend on the temperature, concentration, and starting point in the
phase diagram. The results obtained show that there are severe differences
between the thermodynamically predicted and the kinetically obtained
aggregate structures. The observed differences help to rationalize
the suggestion that monomeric proteins in their native functional
structure can be metastable with respect to the amyloid state, and
that the native fold is a special property that protects them from
aggregation.