P versus Q:: Structural reaction coordinates capture protein folding on smooth landscapes
P versus Q:: Structural reaction coordinates capture protein folding on smooth landscapes
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DOI：
10.1073/pnas.0509768103
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发表时间：
2006-01-17
影响因子：
11.1
通讯作者：
Wolynes, PG
中科院分区：
文献类型：
--
作者：
Cho, SS;Levy, Y;Wolynes, PG
注意你的p和q对蛋白质折叠理论家来说已经变得和那些接受礼仪规则指导的人一样重要。为了评估结构反应坐标在预测蛋白质折叠的过渡态系综（TSE）中的质量，我们将四个结构反应坐标的准确性与动力学测量P-折叠进行了基准测试，P-折叠的值为0.50，定义了两态折叠机制的随机分界线。对于通过简单的双态机制折叠的两种蛋白质，c-src SH 3和Cl-2，通过基于天然拓扑的反应坐标（包括Q，天然接触的分数）预测的TSE的Phi值与基于Pfold的TSE的Phi值几乎相同，相关系数> 0.90。对于具有复杂折叠机制的蛋白质，具有特别宽的，不对称的自由能垒，如设计的3-锚蛋白重复蛋白（3ANK）或具有不同中间体的蛋白质，如cyanovirin-N（CV-N），我们表明，P-折叠= 0.50的结构的集合一般不包括化学相关的过渡态。P折叠的这一弱点限制了它在蛋白质折叠研究中的应用。对于这样的系统，阐明折叠机制的基本特征需要使用多个反应坐标，尽管数量仍然相当少。与此同时，对于简单的折叠机制，没有迹象表明Pfold优于结构上选择的和化学上相关的反应坐标，正确地测量原生性的程度。
Minding your p's and q's has become as important to protein-folding theorists as it is for those being instructed in the rules of etiquette. To assess the quality of structural reaction coordinates in predicting the transition-state ensemble (TSE) of protein folding, we benchmarked the accuracy of four structural reaction coordinates against the kinetic measure P-fold, whose value of 0.50 defines the stochastic separatrix for a two-state folding mechanism. For two proteins that fold by a simple two-state mechanism, c-src SH3 and Cl-2, the Phi-values of the TSEs predicted by native topology-based reaction coordinates (including Q, the fraction of native contacts) are almost identical to those of the TSE based on Pfold, with correlation coefficients of > 0.90. For proteins with complex folding mechanisms that have especially broad, asymmetrical free energy barriers such as the designed 3-ankyrin repeating protein (3ANK) or proteins with distinct intermediates such as cyanovirin-N (CV-N), we show that the ensemble of structures with P-fold = 0.50 generally does not include the chemically relevant transition states. This weakness Of P-fold limits its usefulness in protein folding Studies. For such systems, elucidating the essential features of folding mechanisms requires using multiple reaction coordinates, although the number is still rather small. At the same time, for simple folding mechanisms, there is no indication of superiority for Pfold over structurally chosen and thermodynamically relevant reaction coordinates that correctly measure the degree of nativeness.