Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel.
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel.
Curr Opin Struct Biol. 2020 Aug;63:58-64. doi: 10.1016/j.sbi.2020.04.003. Epub 2020 Jun 5.
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.
我们设计新的或改进的生物分子活性的能力取决于对蛋白质中序列-功能关系的理解。然而，大多数蛋白质的体积大和折叠复杂性掩盖了这些关系，蛋白质优化方法仍然依赖于费力的实验迭代。最近，对稳定性-阈值效应和蛋白质中生物分子上位性作用的作用的更深入了解，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。这些方法能够可靠地甚至一步优化被认为超出计算设计范围的蛋白质的稳定性、表达能力和活性。此外，祖先序列重建产生了关于酶和配体进化中缺失环节的见解，这些见解可用于蛋白质设计。通过系统发育和原子计算的结合，通用计算方法的长期目标是能够普遍应用于研究和优化蛋白质，这一目标似乎终于触手可及。
