Exploring the origins of topological frustration: Design of a minimally frustrated model of fragment B of protein A
Exploring the origins of topological frustration: Design of a minimally frustrated model of fragment B of protein A
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DOI：
10.1073/pnas.96.22.12512
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发表时间：
1999-10-26
影响因子：
11.1
通讯作者：
Brooks, CL
中科院分区：
文献类型：
--
作者：
Shea, JE;Onuchic, JN;Brooks, CL
本文研究了金黄色葡萄球菌蛋白A的螺旋蛋白片段B在非晶格模型中的拓扑受挫现象。该G (o) over波浪型模型表现出设计良好的双态折叠层的热力学和动力学特征，同时具有崩塌和折叠转变，并且在转变温度下具有单指数动力学。拓扑挫折是在没有能量挫折的情况下由费尔希值的分布决定的。拓扑上未受挫的系统在中间phi处呈现单峰分布，而高度受挫的系统在低phi值和高phi值处呈现双峰分布。用热力学和动力学方法测定了蛋白A中phi值的分布。两种方法都得到了以phi = 0.3为中心的单峰分布，尾部延伸到低和高cp值，表明存在少量的拓扑挫折。高phi值的接触点位于螺旋I和II以及螺旋II和II之间的旋转区域，这表明这些发夹在过渡状态下很大程度上是必需的。我们的结果与蛋白质A的全原子模拟以及三字母代码27-mer（可与氧化石墨烯残基螺旋蛋白相比）的晶格模拟非常一致。从全原子模拟中得到的phi值的相对宽的单峰分布和从同一原生折叠的极简模型中得到的phi值表明，过渡态系综的结构主要由蛋白质拓扑决定，而不是能量挫折。
Topological frustration in an energetically unfrustrated off-lattice model of the helical protein fragment B of protein A from Staphylococcus aureus was investigated. This G (o) over tilde-type model exhibited thermodynamic and kinetic signatures of a well-designed two-state folder with concurrent collapse and folding transitions and single exponential kinetics at the transition temperature. Topological frustration is determined in the absence of energetic frustration by the distribution of Fersht phi values. Topologically unfrustrated systems present a unimodal distribution sharply peaked at intermediate phi, whereas highly frustrated systems display a bimodal distribution peaked at low and high phi values. The distribution of phi values in protein A was determined hath thermodynamically and kinetically. Both methods yielded a unimodal distribution centered at phi = 0.3 with tails extending to low and high cp values, indicating the presence of a small amount of topological frustration. The contacts with high phi values were located in the turn regions between helices I and II and II and Ill, intimating that these hairpins are in large part required in the transition state. Our results are in good agreement with all-atom simulations of protein A, as well as lattice simulations of a three- letter code 27-mer (which can be compared with a GO-residue helical protein). The relatively broad unimodal distribution of phi values obtained from the all-atom simulations and that from the minimalist model for the same native fold suggest that the structure of the transition state ensemble is determined mostly by the protein topology and not energetic frustration.