Our ability to design new or improved biomolecular activities depends on understanding the sequence-function relationships in proteins. The large size and fold complexity of most proteins, however, obscure these relationships, and protein-optimization methods continue to rely on laborious experimental iterations. Recently, a deeper understanding of the roles of stability-threshold effects and biomolecular epistasis in proteins has led to the development of hybrid methods that combine phylogenetic analysis with atomistic design calculations. These methods enable reliable and even single-step optimization of protein stability, expressibility, and activity in proteins that were considered outside the scope of computational design. Furthermore, ancestral-sequence reconstruction produces insights on missing links in the evolution of enzymes and binders that may be used in protein design. Through the combination of phylogenetic and atomistic calculations, the long-standing goal of general computational methods that can be universally applied to study and optimize proteins finally seems within reach.

中文翻译：

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结合系统发育和原子计算的实用蛋白质设计方法。

我们设计新的或改进的生物分子活性的能力取决于了解蛋白质中的序列-功能关系。然而，大多数蛋白质的大尺寸和折叠复杂性掩盖了这些关系，蛋白质优化方法继续依赖于费力的实验迭代。最近，对稳定性阈值效应和生物分子上位性在蛋白质中的作用的更深入理解导致了将系统发育分析与原子设计计算相结合的混合方法的发展。这些方法能够对蛋白质的稳定性、可表达性和活性进行可靠甚至单步优化，而这些蛋白质被认为超出了计算设计的范围。此外，祖先序列重建对可用于蛋白质设计的酶和结合剂进化中的缺失环节产生了见解。通过系统发育和原子计算的结合，可以普遍应用于研究和优化蛋白质的通用计算方法的长期目标似乎终于触手可及。