The Occurrence of Biased Conformations as Precursors of Assembly States in Fibril Elongation of Amyloid-beta Fibril Variants: An in Silico Study.

We investigate the prevalence, and so the role in the amyloidogenesis, of biased conformations in large ensembles of monomeric forms for Abeta42 and Abeta40 that can trigger the formation and growth of fibrils described by a dock-lock mechanism. We model such biased conformations as the structural monomeric units that constitute the PDB fibrils 2beg, 2mxu and 2lmn. These units were employed as templates to search for similar structures in statistical conformational ensembles of A$\beta$ peptides generated by molecular dynamics with an accurate force field in explicit solvation, whose high quality is revealed by comparison with Residual Dipolar Coupling (RDC) experiments. The conformational ensembles generated by this intrinsically disordered peptides do not contain conformations highly similar to the amyloidogenic templates. This is a consequence of the low thermodynamic stability exhibited by the template-like conformations. A further constant-pH Monte Carlo study has revealed that this stability can be increased by suitable pH conditions, which helps to trigger the fibril elongation. Moreover, our analyses on the free-energy landscapes, HB prevalences and PCA distributions emphasize the relevance of many-body long-range cooperative interactions, likely acting over the infrequent pre-existing structurally-biased conformations, to explain the fibrils emergence.