IMASL-CONICET, Ejército de Los Andes 950, 5700, San Luis, Argentina.
Eur Biophys J. 2024 Nov;53(7-8):473-480. doi: 10.1007/s00249-024-01725-9. Epub 2024 Oct 23.
The interconnected processes of protein folding, mutations, epistasis, and evolution have all been the subject of extensive analysis throughout the years due to their significance for structural and evolutionary biology. The origin (molecular basis) of epistasis-the non-additive interactions between mutations-is still, nonetheless, unknown. The existence of a new perspective on protein folding, a problem that needs to be conceived as an 'analytic whole', will enable us to shed light on the origin of mutational epistasis at the simplest level-within proteins-while also uncovering the reasons why the genetic background in which they occur, a key component of molecular evolution, could foster changes in epistasis effects. Additionally, because mutations are the source of epistasis, more research is needed to determine the impact of post-translational modifications, which can potentially increase the proteome's diversity by several orders of magnitude, on mutational epistasis and protein evolvability. Finally, a protein evolution thermodynamic-based analysis that does not consider specific mutational steps or epistasis effects will be briefly discussed. Our study explores the complex processes behind the evolution of proteins upon mutations, clearing up some previously unresolved issues, and providing direction for further research.
由于蛋白质折叠、突变、上位性和进化相互关联的过程对于结构和进化生物学具有重要意义，多年来一直是广泛分析的主题。尽管如此，上位性（突变之间非加性相互作用）的起源（分子基础）仍然未知。如果我们能够从一个新的视角来理解蛋白质折叠，将其视为一个“分析整体”，那么我们就能够在最简单的层面上（在蛋白质内部）揭示突变上位性的起源，并揭示为什么遗传背景（分子进化的一个关键组成部分）能够促进上位性效应的变化。此外，由于突变是上位性的来源，因此需要更多的研究来确定翻译后修饰的影响，这些修饰可能会使蛋白质组的多样性增加几个数量级，从而影响突变上位性和蛋白质可进化性。最后，我们将简要讨论一种不考虑特定突变步骤或上位性效应的基于蛋白质进化热力学的分析方法。我们的研究探索了蛋白质在突变时的进化背后的复杂过程，解决了一些以前未解决的问题，并为进一步的研究提供了方向。
