Reframing the Protein Folding Problem: Entropy as Organizer
Reframing the Protein Folding Problem: Entropy as Organizer
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DOI：
10.1021/acs.biochem.1c00687
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发表时间：
2021-12-02
期刊：
影响因子：
2.9
通讯作者：
Rose, George D.
中科院分区：
文献类型：
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作者：
Rose, George D.
长期以来，人们一直认为蛋白质的天然折叠是从大量的构象异构体中通过优化的构象有利的相互作用来选择的。与此形成鲜明对比的是，这一观点引入了一种不同的机制，强调构象熵是蛋白质折叠的主要组织者，同时提出传统观点是不完整的。这种机制源于认识到氢键满足是热力学的必要性。特别地，骨架氢键可能对天然状态的稳定性几乎没有增加，但是完全不满足的骨架氢键将显著地不稳定，将U（nfolded）可逆箭头N（active）平衡向左移动得很远。如果甚至单个骨架极性基团在展开时被溶剂满足，但在折叠时被掩埋而不被满足，则仅该能量罚分（约+5 kcal/mol）将与蛋白质稳定化的几乎整个自由能（通常在生理条件下在-5和-15 kcal/mol之间）相匹敌。因此，在折叠时，掩埋的主链极性基团必须形成氢键，并且它们通过组装α-螺旋和/或β-折叠的链的支架来这样做，除了罕见的例外，氢键供体和受体是完全平衡的唯一构象。此外，对于典型的蛋白质结构域，只有几千个可行的支架拓扑结构是可能的。这一热力学命令通过剔除具有不满足的氢键的构象体来筛选折叠群体，从而降低折叠的熵成本。重要的是，骨架中骨架-骨架氢键所施加的构象限制是不依赖于序列的，从而能够在不牺牲结构的情况下进行突变和进化。
It has been a long-standing conviction that a protein's native fold is selected from a vast number of conformers by the optimal constellation of enthalpically favorable interactions. In marked contrast, this Perspective introduces a different mechanism, one that emphasizes conformational entropy as the principal organizer in protein folding while proposing that the conventional view is incomplete. This mechanism stems from the realization that hydrogen bond satisfaction is a thermodynamic necessity. In particular, a backbone hydrogen bond may add little to the stability of the native state, but a completely unsatisfied backbone hydrogen bond would be dramatically destabilizing, shifting the U(nfolded) reversible arrow N(ative) equilibrium far to the left. If even a single backbone polar group is satisfied by solvent when unfolded but buried and unsatisfied when folded, that energy penalty alone, approximately +5 kcal/mol, would rival almost the entire free energy of protein stabilization, typically between -5 and -15 kcal/mol under physiological conditions. Consequently, upon folding, buried backbone polar groups must form hydrogen bonds, and they do so by assembling scaffolds of alpha-helices and/or strands of beta-sheet, the only conformers in which, with rare exception, hydrogen bond donors and acceptors are exactly balanced. In addition, only a few thousand viable scaffold topologies are possible for a typical protein domain. This thermodynamic imperative winnows the folding population by culling conformers with unsatisfied hydrogen bonds, thereby reducing the entropy cost of folding. Importantly, conformational restrictions imposed by backbone-backbone hydrogen bonding in the scaffold are sequence-independent, enabling mutation-and thus evolution-without sacrificing the structure.