De novo protein design, a retrospective.

IF 7.2 2区 生物学 Q1 BIOPHYSICS
Ivan V Korendovych, William F DeGrado
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引用次数: 93

Abstract

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, or de 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 in de novo protein 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 in de novo design 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 novo design 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.

从头开始的蛋白质设计,回顾。
蛋白质是分子机器,其功能取决于其实现具有精确定义的结构和动态特性的复杂折叠的能力。从第一性原理或从头开始合理设计蛋白质曾经被认为是不可能的,但今天,具有各种折叠和功能的蛋白质已经实现。我们回顾了该领域的早期发展,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的基本原理的理解,并为具有前所未有的结构和性质的大分子的设计提供了信息。从头开始的蛋白质设计的最初里程碑集中在构建在水和膜中折叠以采用折叠构象的序列上。第一批蛋白质是用非常简单的物理模型根据第一性原理设计出来的。随着计算机变得越来越强大,利用旋转体近似可以发现稳定所需折叠的氨基酸序列。随着蛋白质结构的晶体学数据库在随后几年的扩展,通过组装在自然界中频繁出现的短骨架片段来构建蛋白质成为可能。从头设计的第二个里程碑涉及复杂功能的发现。蛋白质被设计成结合各种金属、卟啉和其他辅助因子。催化水解和氧依赖反应的蛋白质的设计已经取得了重大进展。然而,重新设计能量要求高的反应催化剂,甚至是高亲和力和特异性结合高功能化复杂极性分子的蛋白质,仍然是一个重要的挑战,现在正在实现。最后,蛋白质的设计对我们对膜蛋白折叠和离子跨膜运输的理解做出了重大贡献。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,现在正变得越来越有可能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Quarterly Reviews of Biophysics
Quarterly Reviews of Biophysics 生物-生物物理
CiteScore
12.90
自引率
1.60%
发文量
16
期刊介绍: Quarterly Reviews of Biophysics covers the field of experimental and computational biophysics. Experimental biophysics span across different physics-based measurements such as optical microscopy, super-resolution imaging, electron microscopy, X-ray and neutron diffraction, spectroscopy, calorimetry, thermodynamics and their integrated uses. Computational biophysics includes theory, simulations, bioinformatics and system analysis. These biophysical methodologies are used to discover the structure, function and physiology of biological systems in varying complexities from cells, organelles, membranes, protein-nucleic acid complexes, molecular machines to molecules. The majority of reviews published are invited from authors who have made significant contributions to the field, who give critical, readable and sometimes controversial accounts of recent progress and problems in their specialty. The journal has long-standing, worldwide reputation, demonstrated by its high ranking in the ISI Science Citation Index, as a forum for general and specialized communication between biophysicists working in different areas. Thematic issues are occasionally published.
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