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We studied the refolding free energy landscape of 26 proteins using the Go-like model. The distance between the denaturated state and the transition state, XF, was calculated using the Bell theory and the nonlinear Dudko-Hummer-Szabo theory, and its relation to the geometrical properties of the native state was considered in detail. We showed that none of the structural parameters, such as the contact order, protein length, and radius of cross section, correlate with XF for all classes of proteins. To overcome this problem, we have introduced the nematic order parameter P02, which describes the ordering of the structured elements of the native state. Due to its topologically global nature, P02 is better than other structural parameters in describing the folding free energy landscape. In particular, P02 displays a good correlation with XF extracted from the nonlinear theory for all three classes of proteins. Therefore, this parameter can be used to predict XF for any protein, if its native structure is known. [ABSTRACT FROM AUTHOR]

Fibril formation resulting from protein misfolding and aggregation is a hallmark of several neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Despite much progress in the understanding of the protein aggregation process, the factors governing fibril formation rates and fibril stability have not been fully understood. Using lattice models, we have shown that the fibril formation time is controlled by the kinetic stability of the fibril state but not by its energy. Having performed all-atom explicit solvent molecular dynamics simulations with the GROMOS43a1 force field for full-length amyloid beta peptides Aβ40 and Aβ42 and truncated peptides, we demonstrated that kinetic stability can be accessed via mechanical stability in such a way that the higher the mechanical stability or the kinetic stability, the faster the fibril formation. This result opens up a new way for predicting fibril formation rates based on mechanical stability that may be easily estimated by steered molecular dynamics. [ABSTRACT FROM AUTHOR]