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Abstract:
Since the time of the Last Universal Common Ancestor (LUCA), proteins have been the fundamental catalysts of life. However, for their activity they must assume three-dimensional structures by a complex, easily disrupted, process of folding. Thus, it is still unclear how the first folded proteins
emerged and how life came to rely so extensively on their ability to fold. Our hypothesis is that the first folded proteins resulted from the increased complexity of peptides in the “RNA-peptide world” that preceded LUCA, possibly by three mechanisms [1-2]: repetition, accretion, and recombination. By now, repetition and accretion have been explored with success, but recombination has so far remained poorly studied. Due to its centrality to all processes of life and its very slow rate of change, the ribosome is the main survivor of the primordial “RNA-peptide world” and its proteins offer a window onto the time when
polypeptide chains learned to fold [1]. Following a computational approach, we evaluated the propensity of different ribosomal fragments, which are intrinsically disordered and adopt regular structures only within a scaffold, to establish geometrically and energetically compatible interfaces that would allow the formation of stable, globular, recombinant folds in the absence of RNA. As a result, we identified more than 200 ribosomal fragment pairs that can recreate not only frequent protein folds but also novel fold topologies, opening a door to a better understanding of the emergence of the first autonomously folding proteins.
