Evolutionary Optimization of Protein Folding

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.

自38亿年前蛋白质诞生以来，自然塑造了其组成结构。然而，造就蛋白质非凡多样性的结构改变的根本驱动因素，仍有待阐明。本研究探讨蛋白质进化是否会影响折叠速率。我们直接基于经尺寸校正的接触序（size-modified contact order），估算了当前已收录的全部蛋白质结构域（protein domains）的折叠时长。这些数值被映射至蛋白质结构域出现的进化时序，该时序源自对989个全测序基因组中蛋白质结构域的系统基因组学分析（phylogenomic analysis）。研究结果显示，进化过程中折叠速率整体呈现显著上升趋势，已知的超快速下坡折叠蛋白（ultra-fast downhill folders）在该进化时序中出现的时间相对较晚。值得注意的是，折叠优化依赖于蛋白质二级结构。α折叠（alpha-folds）在整个进化历程中均呈现出折叠速率提升的趋势，而β折叠（beta-folds）则在始于结构域组合“大爆发”的过去15亿年间，出现了折叠时长增加的趋势。因此，当前这类结构域的平均折叠速度较慢。本研究结果表明，结构域的快速高效折叠塑造了蛋白质结构的全域集合。这一发现支持如下假说：优化天然构象（native fold）的动力学与热力学可及性，能够降低妨碍细胞正常功能的蛋白质聚集倾向（aggregation propensities）。