Stunning advances have been achieved in addressing the protein folding problem, providing deeper understanding of the mechanisms by which proteins navigate energy landscapes to reach their native states and enabling powerful algorithms to connect sequence to structure. However, the realities of the in vivo protein folding problem remain a challenge to reckon with. Here, we discuss the concept of the “proteome folding problem”—the problem of how organisms build and maintain a functional proteome—by admitting that folding energy landscapes are characterized by many misfolded states and that cells must deploy a network of chaperones and degradation enzymes to minimize deleterious impacts of these off-pathway species. The resulting proteostasis network is an inextricable part of in vivo protein folding and must be understood in detail if we are to solve the proteome folding problem. We discuss how the development of computational models for the proteostasis network’s actions and the relationship to the biophysical properties of the proteome has begun to offer new insights and capabilities.

在解决蛋白质折叠问题方面取得了惊人的进展，提供了对蛋白质导航能量景观以达到其天然状态的机制的更深入理解，并使强大的算法能够将序列与结构联系起来。然而，体内蛋白质折叠问题的现实仍然是一个不容忽视的挑战。在这里，我们讨论了“蛋白质组折叠问题”的概念——生物体如何构建和维持功能性蛋白质组的问题——承认折叠能量景观以许多错误折叠状态为特征，并且细胞必须部署一个由伴侣和降解酶组成的网络以尽量减少这些偏离途径物种的有害影响。由此产生的蛋白质稳态网络是体内蛋白质折叠不可分割的一部分，如果我们要解决蛋白质组折叠问题，就必须对其进行详细了解。我们讨论了蛋白质稳态网络行为的计算模型的发展以及与蛋白质组的生物物理特性的关系如何开始提供新的见解和能力。