Evolutionary optimization of protein folding

Abstract

Nature has shaped the make up of proteins since their appearance, [Formula: see text]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 a 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 [Formula: see text]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.

Figure 1. Protein topologies that favor short range inter-aminoacid contacts might be the result of an evolutionary optimization of foldability and thus would have likely appeared late in evolution.

Figure 2. Change in length and foldability during evolution: a) Size Modified Contact Order (SMCO) versus approximative F domain age in billion of years (Gya).

Each data point represents an SMCO average of domain belonging to the same F. Triangles show SMCO averages for domains belonging to the same F and experimentally known to be ultra-fast folders . b) Average amino-acid chain length for domains belonging to the same F versus F domain age in Gya. The solid line shows a LOESS polynomial regression, and the grey shade the 95% confidence interval.

Figure 3. Change in foldability during evolution for subsets of chain size: Distribution of domain length for domains appearing a) 3.8-1.5 Gya and b) 1.5-0 Gya.

Abundancies were colored according to the average SMCO, the difference between the end points of the polynomial regression of SMCO in this dataset, for the specified initial (a) and later (b) time period. Yellow to red indicates a decrease, and blue an increase in SMCO. The barplots (inset) show the percentage of domains with positive (blue), negative (yellow), and insignificant (green) SMCO.

Figure 4. Percentage of all domains with a positive (blue), negative (yellow), and insignificant (green) SMCO.

a) for 3.8-1.5 Gya, and b) 1.5-0 Gya. Each barplot considers one of the four fold classes according to their secondary structure: all-, all-, /, and +, as indicated. The barplots were obtained from domain length distributions analogous to those shown in Figure S3.