Skolnick J, Kolinski A, Yaris R
Department of Chemistry, Washington University, Saint Louis, MO 63130.
Proc Natl Acad Sci U S A. 1988 Jul;85(14):5057-61. doi: 10.1073/pnas.85.14.5057.
With the use of dynamic Monte Carlo simulations, the necessary conditions for the collapse from a random-coil denatured state to a structurally unique four-member beta-barrel native state of a model globular protein have been investigated. These systems are free to roam through all of configuration space--both native and nonnative interactions are allowed. The relative importance of hydrophobic and hydrophilic interactions and the presence or absence of statistical bend-forming regions for the formation of a unique native state are examined, and the conditions necessary for a denatured-to-native (and vice versa) conformational transition that is thermodynamically all-or-none and which always results in collapse to the same, four-member beta-barrel are explored. These conditions are found to be a general pattern of hydrophobic/hydrophilic residues that allows the native state to differentiate the interior from the exterior of the protein and the presence of regions that are, at the very least, neutral toward turn formation. The former set of interactions seems to define the mean length of the beta-stretch, and the latter set serves to lock the native state into the lowest free energy state, the native conformation. These folding simulations strongly suggest that the general rules of protein folding are rather robust and that site-specific tertiary interactions are only involved in structural fine tuning. The conditions required for the formation of a structurally unique native state from a manifold of collapsed conformations that are originally quite close in energy is highly suggestive of a mechanism of protein evolution by means of random mutations. The implications of these folding studies for such a mechanism are qualitatively explored.
通过动态蒙特卡罗模拟，研究了模型球状蛋白从无规卷曲变性状态折叠成结构独特的四聚体β桶状天然状态的必要条件。这些系统可以在所有构象空间中自由探索——既允许天然相互作用，也允许非天然相互作用。研究了疏水相互作用和亲水相互作用的相对重要性，以及形成独特天然状态时统计性弯曲形成区域的有无，并探索了变性到天然（反之亦然）构象转变所需的条件，这种转变在热力学上是全或无的，并且总是导致折叠成相同的四聚体β桶状结构。发现这些条件是疏水/亲水残基的一种普遍模式，它使天然状态能够区分蛋白质的内部和外部，以及至少对转角形成呈中性的区域的存在。前一组相互作用似乎决定了β链的平均长度，而后一组相互作用则将天然状态锁定在最低自由能状态，即天然构象。这些折叠模拟强烈表明，蛋白质折叠的一般规则相当稳健，位点特异性三级相互作用仅参与结构微调。从最初能量相当接近的大量折叠构象中形成结构独特的天然状态所需的条件，强烈暗示了通过随机突变进行蛋白质进化的机制。定性地探讨了这些折叠研究对这种机制的影响。
