´ ` ´ ¨ Cedric Debes1, Minglei Wang2, Gustavo Caetano-Anolles2*, Frauke Grater1,3* 1 Heidelberg Institute for Theoretical Studies, Heidelberg, Germany, 2 Evolutionary Bioinformatics Laboratory, Department of Crop Sciences, University of Illinois, Urbana, Illinois, United States of America, 3 CAS-MPG Partner Institute and Key Laboratory for Computational Biology, Shanghai, China
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. `s ´s ¨ Citation: Debe C, Wang M, Caetano-Anolle G, Grater 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 `s Copyright: ß 2013 Debe 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. * E-mail: firstname.lastname@example.org (GCA); email@example.com (FG)
The catalog of naturally occurring protein structures  exhibits a large disparity of folding times (from microseconds , to hours ). This disparity is the result of roughly *3.8 billion years of evolution during which new protein structures were created and optimized. The evolutionary processes driving the discovery and optimization of protein topologies is complex and remains to be fully understood. Nature probably uncovers new topologies in order to fulfill new functions, and optimizes existing topologies to increase their performance. Various physical and chemical requirements, from foldability to structural stability, are likely to be additional players shaping protein structure evolution. One indicator for foldability, i.e. the ease of taking up the native protein fold, is a short folding time. Here we propose that foldability is a constraint that crucially contributes to evolutionary history. Optimization of foldability during evolution could explain the existence of a folding funnel [4,5], into which a defined set of folding pathways lead to the native state, as postulated early on...