Franco Simonetti1, Edgar Chacon1, Maria Freiberger2, Leandro Radusky3, Alexander Monzon4, Diego Ferreiro5 and R. Gonzalo Parra1*
1Barcelona Supercomputing Center
2Institut de Biologie Paris Seine, Sorbonne Université
3Mimark Diagnostics
4Universidad de Padova
5Universidad de Buenos Aires
parra.gonzalo [at] gmail.com
Abstract
Globular protein domains satisfy the principle of minimal frustration, and thus their folding landscapes are strongly funneled towards their native state with residual energetic conflicts often associated with function. In contrast, intrinsically disordered proteins populate heterogeneous conformational ensembles as a consequence of competing interactions and therefore flatter energy landscapes. Still, the specific energetic signatures that lead to protein disorder are poorly understood. Here we characterized the local frustration patterns of 3,176 proteins and 59,627 conformers spanning different flavours of intrinsic disorder. We found that in the case of direct residue-residue interactions, except for a minor contribution of specific interaction types, disordered residues are not excessively highly frustrated; instead, they are enriched in neutrally frustrated interactions and a reduced prevalence of minimally frustrated ones. Furthermore, we found that the most distinguishable feature between ordered and disordered residues comes from long range interactions where disordered residues are depleted of stabilizing interactions and enriched in energetic conflicts. When disordered regions are analysed in complex with known protein partners, their energetic profiles resemble those of ordered residues. We conclude that intrinsic disorder is not a consequence of excessive energetic conflicts as believed for the case of statistical random heteropolymers. Instead, disordered proteins exist at the edge of foldability, where a small number of stabilizing interactions with other proteins or substrates can shift their equilibrium towards more structured, functional conformations.
Keywords: protein folding, function, disorder