Ensembles from ordered and disordered proteins reveal similar structural constraints during evolution

Abstract

Inter-residue contacts determine the structural properties for each conformer in the ensembles describing the native state of proteins. Structural constraints during evolution could then provide biologically relevant information about the conformational ensembles and their relationship with protein function. Here, we studied the proportion of sites evolving under structural constraints in two very different types of ensembles, those coming from ordered or disordered proteins. Using a structurally constrained model of protein evolution we found that both types of ensembles show comparable, near 40%, number of positions evolving under structural constraints. Among these sites, ~68% are in disordered regions and ~57% of them show long-range inter-residue contacts. Also, we found that disordered ensembles are redundant in reference to their structurally constrained evolutionary information and could be described on average with ~11 conformers. Despite the different complexity of the studied ensembles and proteins, the similar constraints reveal a comparable level of selective pressure to maintain their biological functions.These results highlight the importance of the evolutionary information to recover meaningful biological information to further characterize conformational ensembles.

Intrinsically Disordered Protein Ensembles Shape Evolutionary Rates Revealing Conformational Patterns

“…The best correlations are found by combining a small (<8) number of conformers rather than the whole ensemble, reflecting distinct contributions of preferred conformations, possibly related to the structure-function relationship of the protein 33,34 . These results agree with previous works describing IDP ensembles as highly redundant 25 and open the opportunity for the development of bioinformatics tools to curate IDPs ensembles databases 35 . Largely ignored in evolutionary studies, except for a few exceptions (for example see [36][37][38] ), contact variations due to .…”

“…In a previous work we found that IDP ensembles are redundant in terms of their structural constraints on evolution, since ~10 conformers are required on average to explain the structural constraints observed in homologous alignments of IDPs 25 . Following this idea, we explored all possible combinations of different numbers of conformers from each ensemble to study if there is a particular subset of conformers establishing contacts that better explain the evolutionary rate profiles.…”

“…Early studies showed that IDPs and disordered regions evolve faster than ordered proteins 22 , as expected from their low number of contacts per site 23 and high solvent exposure 13 . Although previous works have detected structurally constrained evolutionary patterns in IDPs [24][25][26] , their role with IDPs typical higher flexibility remains unclear. In proteins with a significant degree of conformational diversity like IDPs, it could also be expected that different partially folded conformers with transient secondary structure elements or preferred conformations in the ensemble may impose specific and additive constraints on per-site evolutionary rates.…”

Intrinsically disordered protein ensembles shape evolutionary rates revealing conformational patterns

“…The best correlations are found by combining a small (<8) number of conformers rather than the whole ensemble, reflecting distinct contributions of preferred conformations, possibly related to the structure-function relationship of the protein 33,34 . These results agree with previous works describing IDP ensembles as highly redundant 25 and open the opportunity for the development of bioinformatics tools to curate IDPs ensembles databases 35 . Largely ignored in evolutionary studies, except for a few exceptions (for example see [36][37][38] ), contact variations due to conformational changes are revealed as impossible to neglect in IDP ensembles.…”