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CONSERVED RESIDUES AND THE MECHANISM OF PROTEIN FOLDING

机译：保留残基和蛋白质折叠的机理

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EXPERIMENTAL(1-6) and simulation(7) studies show that small monomeric proteins fold in one kinetic step, which entails overcoming the free-energy barrier between the unfolded and the native protein through a transition state(8,9). Two models of transition state formation have been proposed: a 'nonspecific' one in which it depends on the formation of a sufficient number of native-like contacts regardless of what amino acids are involved(10-12) and a 'specific' one, in which it depends on formation of a specific subset of the native structure (a folding nucleus)(8,13,14). The latter requires that some amino acids form most of their contacts in the transition state, whereas others only do so on reaching the native conformation. If so, mutations affecting the stability of the transition state nucleus should have a greater effect on the folding kinetics than mutations elsewhere, and the residues involved should be evolutionarily conserved. Lattice-model simulations and experiments(8,13-16) suggest that such mutations exist. Here we present a method for determining the folding nucleus of a protein with known structure with two-state folding kinetics. This method is based on the alignment of many sequences designed to fold into the native conformation of a protein to identify the positions where amino acids are most conserved in designed sequences. The method is applied to chymotrypsin inhibitor 2 (CI2), a protein whose transition state has been previously studied by protein engineering(14-16). The involvement of residues in folding nucleus of CI2 is clearly correlated with their conservation in design, and the residues forming the nucleus are highly conserved in 23 natural sequences homologous to CI2. [References: 31]
机译：实验（1-6）和模拟（7）研究表明，小的单体蛋白在一个动力学步骤中折叠，这需要通过过渡状态克服未折叠蛋白和天然蛋白之间的自由能垒（8,9）。已经提出了两种过渡态形成模型：一种“非特异性”模型，其中依赖于足够数量的天然样接触的形成而与所涉及的氨基酸无关（10-12），以及一种“特异性”模型，其中取决于天然结构的特定子集（折叠核）的形成（8,13,14）。后者要求某些氨基酸以过渡状态形成其大部分接触，而其他氨基酸仅在达到天然构象时才形成。如果是这样，那么影响过渡态原子核稳定性的突变对折叠动力学的影响应比其他地方的突变更大，并且涉及的残基应在进化上保守。格模型仿真和实验（8,13-16）表明存在这样的突变。在这里，我们介绍一种确定具有两个状态折叠动力学的已知结构的蛋白质的折叠核的方法。该方法基于许多设计为折叠成蛋白质天然构象的序列的比对，以鉴定在设计序列中氨基酸最保守的位置。该方法适用于胰凝乳蛋白酶抑制剂2（CI2），该蛋白的过渡状态先前已经通过蛋白质工程学进行了研究（14-16）。残基在CI2折叠核中的参与与它们在设计中的保守性显然相关，并且形成核的残基在与CI2同源的23个自然序列中高度保守。 [参考：31]

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