Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA.
Mol Biol Evol. 2019 Sep 1;36(9):1955-1963. doi: 10.1093/molbev/msz119.
The protein misfolding avoidance hypothesis explains the universal negative correlation between protein abundance and sequence evolutionary rate across the proteome by identifying protein folding free energy (ΔG) as the confounding variable. Abundant proteins resist toxic misfolding events by being more stable, and more stable proteins evolve slower because their mutations are more destabilizing. Direct supporting evidence consists only of computer simulations. A study taking advantage of a recent experimental breakthrough in measuring protein stability proteome-wide through melting temperature (Tm) (Leuenberger et al. 2017), found weak misfolding avoidance hypothesis support for the Escherichia coli proteome, and no support for the Saccharomyces cerevisiae, Homo sapiens, and Thermus thermophilus proteomes (Plata and Vitkup 2018). I find that the nontrivial relationship between Tm and ΔG and inaccuracy in Tm measurements by Leuenberger et al. 2017 can be responsible for not observing strong positive abundance-Tm and strong negative Tm-evolutionary rate correlations.
蛋白质错误折叠避免假说通过将蛋白质折叠自由能（ΔG）确定为混杂变量，解释了蛋白质丰度和序列进化率在整个蛋白质组中普遍存在的负相关关系。丰富的蛋白质通过更加稳定来抵抗有毒的错误折叠事件，而更稳定的蛋白质进化速度更慢，因为它们的突变更不稳定。直接支持证据仅包括计算机模拟。一项利用最近在通过熔点（Tm）测量蛋白质稳定性方面取得的实验突破的研究（Leuenberger 等人，2017 年），对大肠杆菌蛋白质组的错误折叠避免假说提供了微弱的支持，而对酿酒酵母、智人和嗜热栖热菌蛋白质组没有支持（Plata 和 Vitkup，2018 年）。我发现，Tm 和 ΔG 之间的非平凡关系以及 Leuenberger 等人 2017 年 Tm 测量的不准确性可能导致没有观察到强烈的丰度-Tm 和强烈的负 Tm-进化率相关性。
