Otimização evolutiva do dobramento das proteínas

Evolutionary Optimization of Protein Folding

Cédric Debès, Minglei Wang, Gustavo Caetano-Anollés, Frauke Gräter 

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 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 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.

Author Summary

Nature has come up with an enormous variety of protein three-dimensional structures, each of which is thought to be optimized for its specific function. A fundamental biological endeavor is to uncover the driving evolutionary forces for discovering and optimizing new folds. A long-standing hypothesis is that fold evolution obeys constraints to properly fold into native structure. We here test this hypothesis by analyzing trends of proteins to fold fast during evolution. Using phylogenomic and structural analyses, we observe an overall decrease in folding times between 3.8 and 1.5 billion years ago, which can be interpreted as an evolutionary optimization for rapid folding. This trend towards fast folding probably resulted in manifold advantages, including high protein accessibility for the cell and a reduction of protein aggregation during misfolding.

Citation: Debès C, Wang M, Caetano-Anollés G, Gräter F (2013) Evolutionary Optimization of Protein Folding. PLoS Comput Biol 9(1): e1002861. doi:10.1371/journal.pcbi.1002861

Editor: Ruth Nussinov, National Cancer Institute, United States of America and Tel Aviv University, Israel

Received: July 3, 2012; Accepted: November 9, 2012; Published: January 17, 2013

Copyright: © 2013 Debès et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was supported by the National Science Foundation (Grant MCB-0749836 to GCA) and the Klaus Tschira Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

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