当前位置: X-MOL 学术Q. Rev. Biophys. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
De novoprotein design, a retrospective
Quarterly Reviews of Biophysics ( IF 6.1 ) Pub Date : 2020-02-11 , DOI: 10.1017/s0033583519000131
Ivan V Korendovych 1 , William F DeGrado 2
Affiliation  

Proteins are molecular machines whose function depends on their ability to achieve complex folds with precisely defined structural and dynamic properties. The rational design of proteins from first-principles, orde novo, was once considered to be impossible, but today proteins with a variety of folds and functions have been realized. We review the evolution of the field from its earliest days, placing particular emphasis on how this endeavor has illuminated our understanding of the principles underlying the folding and function of natural proteins, and is informing the design of macromolecules with unprecedented structures and properties. An initial set of milestones inde novoprotein design focused on the construction of sequences that folded in water and membranes to adopt folded conformations. The first proteins were designed from first-principles using very simple physical models. As computers became more powerful, the use of the rotamer approximation allowed one to discover amino acid sequences that stabilize the desired fold. As the crystallographic database of protein structures expanded in subsequent years, it became possible to construct proteins by assembling short backbone fragments that frequently recur in Nature. The second set of milestones inde novodesign involves the discovery of complex functions. Proteins have been designed to bind a variety of metals, porphyrins, and other cofactors. The design of proteins that catalyze hydrolysis and oxygen-dependent reactions has progressed significantly. However,de novodesign of catalysts for energetically demanding reactions, or even proteins that bind with high affinity and specificity to highly functionalized complex polar molecules remains an importnant challenge that is now being achieved. Finally, the protein design contributed significantly to our understanding of membrane protein folding and transport of ions across membranes. The area of membrane protein design, or more generally of biomimetic polymers that function in mixed or non-aqueous environments, is now becoming increasingly possible.

中文翻译:

从头蛋白设计,回顾

蛋白质是分子机器,其功能取决于它们实现具有精确定义的结构和动态特性的复杂折叠的能力。从第一性原理合理设计蛋白质,或从头,曾经被认为是不可能的,但今天已经实现了具有多种折叠和功能的蛋白质。我们回顾了该领域最早的发展历程,特别强调了这一努力如何阐明了我们对天然蛋白质折叠和功能原理的理解,并为具有前所未有的结构和特性的大分子设计提供了信息。一组初始里程碑从头蛋白质设计的重点是构建在水和膜中折叠以采用折叠构象的序列。第一种蛋白质是根据第一原理使用非常简单的物理模型设计的。随着计算机变得越来越强大,旋转异构体近似的使用使人们能够发现稳定所需折叠的氨基酸序列。随着随后几年蛋白质结构晶体学数据库的扩展,通过组装在自然界中经常出现的短骨架片段来构建蛋白质成为可能。第二组里程碑从头设计涉及复杂功能的发现。蛋白质已被设计用于结合多种金属、卟啉和其他辅助因子。催化水解和氧依赖性反应的蛋白质的设计取得了显着进展。然而,从头设计用于高能反应的催化剂,甚至是与高度功能化的复杂极性分子具有高亲和力和特异性的蛋白质,仍然是目前正在实现的重要挑战。最后,蛋白质设计极大地促进了我们对膜蛋白折叠和离子跨膜转运的理解。膜蛋白设计领域,或者更一般地说,在混合或非水环境中起作用的仿生聚合物领域,现在变得越来越可能。
更新日期:2020-02-11
down
wechat
bug