Principles for designing ideal protein structures

摘要

当天然蛋白能够折叠成具有生物适应力的独特rn结构时，尽管可能会出现很多从能量角度来说rn对其不利的、非理想的特征(比如说纠结在一rn起的螺旋体、紧绷的环和被埋没的极性基)，rn它们也会这么做。这些特征在蛋白中出现是由rn于对生物功能的演化选择，或是由于中性偏rn移。在这项研究中，作者介绍了设计理想蛋白rn结构的一个新方法，完全一致的局部和非局部rn相互作用可以使所设计出的蛋白结构稳定。他rn们总结出将二级结构的蛋白与蛋白的三级主题rn关联起来的一套简单“规则”，并用这些规则rn来设计可折叠成更复杂蛋白结构的序列。这里rn所介绍的设计原理和方法将让研究人员能够为rn下一代人造功能蛋白设计出一系列可靠、稳定rn的蛋白构件。%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 a helices, bulged p-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 Meal protein structures consisting of a-helices, p-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.