Evolutionary Optimization of Protein Folding

Cédric Debès, Minglei Wang, Gustavo Caetano-Anollés, Frauke Gräter, Ruth Nussinov
2013 PLoS Computational Biology  
Nature has shaped the make up of proteins since their appearance, *3.8 billion years ago. However, the fundamental drivers of structural change responsible for the extraordinary diversity of proteins have yet to be elucidated. Here we explore if protein evolution affects folding speed. We estimated folding times for the present-day catalog of protein domains directly from their size-modified contact order. These values were mapped onto an evolutionary timeline of domain appearance derived from
more » ... phylogenomic analysis of protein domains in 989 fully-sequenced genomes. Our results show a clear overall increase of folding speed during evolution, with known ultra-fast downhill folders appearing rather late in the timeline. Remarkably, folding optimization depends on secondary structure. While alpha-folds showed a tendency to fold faster throughout evolution, beta-folds exhibited a trend of folding time increase during the last *1.5 billion years that began during the "big bang" of domain combinations. As a consequence, these domain structures are on average slow folders today. Our results suggest that fast and efficient folding of domains shaped the universe of protein structure. This finding supports the hypothesis that optimization of the kinetic and thermodynamic accessibility of the native fold reduces protein aggregation propensities that hamper cellular functions.
doi:10.1371/journal.pcbi.1002861 pmid:23341762 pmcid:PMC3547816 fatcat:jdsqfq2g2fdgpaomcwetpzgyi4