来自华盛顿大学的David Baker实验室小组通过遵循他们设定的一套规则,成功的从头设计了五种蛋白,这些蛋白可以确实地折叠成预期的构象。在一项盲测试中,研究小组证实这些合成蛋白与预期结构密切匹配。

-2012年11月8日《自然》

中文翻译


【题目】蛋白质理想结构的设计原则

【译文】与随机杂聚物不同,自然蛋白能够折叠成独特的有序结构。这些蛋白质的氨基酸序列编码规律是很难理解的,主要是因为它们具有不宜的非理想特征,例如,扭结的α螺旋、突出的β折叠、紧密的杂环以及埋入的极性基团。这些特征通过生物功能的进化选择或中性漂变在蛋白中形成。本研究开发了一种设计蛋白质理想结构的方法,利用蛋白质中的局部和非局部的相互作用来维持蛋白质的结构稳定。该方法基于将二级结构模式与蛋白三级基序联系的一系列法则,使得设计漏斗形状蛋白折叠能量塔以形成靶折叠状态变为可能。依据这些法则,我们设计出能够折叠成理想蛋白结构的序列,这种结构由α螺旋、β折叠和最小限度杂环组成。发现为5种不同拓扑结构的设计是单体的,而且非常稳定,形成的结构分辨率接近计算机模型。这些结果阐明了自然蛋白是如何产生折叠漏斗的,并为人工改造无自然进化的功能蛋白提供了基础。

英文原稿


[Title]: Principles for designing ideal protein structures

[Authors]:Nobuyasu Koga,1, 4 Rie Tatsumi-Koga,1, 4 Gaohua Liu,2, 3, 4 Rong Xiao,2, 3 Thomas B. Acton,2, 3 Gaetano T. Montelione2, 3 & David Baker1

[Abstract]:Unlike random heteropolymers, natural proteins fold into unique ordered structures. Understanding how these are encoded in amino-acid sequences is complicated by energetically unfavourable non-ideal features—for example kinked α-helices, bulged β-strands, strained loops and buried polar groups—that arise in proteins from evolutionary selection for biological function or from neutral drift. Here we describe an approach to designing ideal protein structures stabilized by completely consistent local and non-local interactions. The approach is based on a set of rules relating secondary structure patterns to protein tertiary motifs, which make possible the design of funnel-shaped protein folding energy landscapes leading into the target folded state. Guided by these rules, we designed sequences predicted to fold into ideal protein structures consisting of α-helices, β-strands and minimal loops. Designs for five different topologies were found to be monomeric and very stable and to adopt structures in solution nearly identical to the computational models. These results illuminate how the folding funnels of natural proteins arise and provide the foundation for engineering a new generation of functional proteins free from natural evolution.

原文地址

http://www.nature.com/nature/journal/v491/n7423/full/nature11600.html

 

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