Principles for designing ideal protein structures.
Principles for designing ideal protein structures.
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与随机杂聚物不同，天然蛋白质折叠成独特的有序结构。了解这些是如何在氨基酸序列中编码的是复杂的，因为能量上不利的非理想特征，例如扭结的α-螺旋，凸起的β-链，紧张的环和埋藏的极性基团，这些特征在蛋白质中产生于生物功能的进化选择或中性漂移。在这里，我们描述了一种设计通过完全一致的局部和非局部相互作用稳定的理想蛋白质结构的方法。该方法是基于一组规则的二级结构模式的蛋白质三级基序，这使得可能的漏斗形蛋白质折叠能量景观的设计，导致目标折叠状态。在这些规则的指导下，我们设计了预测折叠成由α-螺旋、β-链和最小环组成的理想蛋白质结构的序列。五个不同的拓扑结构的设计被发现是单体和非常稳定的，并采用几乎相同的计算模型的解决方案中的结构。这些结果阐明了天然蛋白质的折叠漏斗是如何产生的，并为工程设计新一代不受自然进化影响的功能蛋白质提供了基础。
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.