SIDE-CHAIN ENTROPY OPPOSES ALPHA-HELIX FORMATION BUT RATIONALIZES EXPERIMENTALLY DETERMINED HELIX-FORMING PROPENSITIES
SIDE-CHAIN ENTROPY OPPOSES ALPHA-HELIX FORMATION BUT RATIONALIZES EXPERIMENTALLY DETERMINED HELIX-FORMING PROPENSITIES
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DOI：
10.1073/pnas.89.13.5937
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发表时间：
1992-07-01
影响因子：
11.1
通讯作者：
ROSE, GD
中科院分区：
文献类型：
--
作者：
CREAMER, TP;ROSE, GD
在最近的宿主-客体研究中，氨基酸残基的螺旋形成倾向已通过三组进行了定量，每组都获得了相似的结果[Padmanabhan, S., Marqusee, S., Ridgeway, T., Laue, T. M. & Baldwin, R. L. (1990) Nature (London) 344, 268-270; O'Neil, K. T. 和 DeGrado, W. F. (1990) Science 250, 646-651； Lyu, P. C.、Liff, M. I.、Marky, L. A. 和 Kallenbach, N. R. (1990) Science 250, 669-673]。在这里，我们探讨了这样一个假设：这些测量到的螺旋形成倾向主要是由于螺旋本身对残基侧链施加的构象限制。通过计算庞大的螺旋主链“冻结”螺旋侧链中可用自由度的程度来检验该命题。具体来说，对于一系列非极性残基，通过简单的蒙特卡罗计算获得展开状态和α螺旋状态下的每个侧链之间构型熵的差异DELTA-S。然后将这些计算出的熵差与实验确定的值进行比较。发现天然存在的氨基酸的测量值和计算值非常一致，而非天然氨基酸的测量值和计算值完全不一致。计算中，DELTA-S(Ala) = 0。所考虑的一系列天然非极性侧链的熵损失顺序为Ala < Leu < Trp < Met < Phe < Ile < Tyr < Val。其中，没有一个有利于螺旋的形成；丙氨酸呈中性，其余残留物均不同程度不利。因此，应用于侧链时，术语“螺旋优先”是用词不当。虽然侧链-侧链相互作用在某些情况下可能会调节稳定性，但我们的结果表明形成螺旋的驱动力必须起源于主链，这与四十年前鲍林的观点一致[Pauling, L., Corey, R. B. & Branson, H. R. (1951) Proc.国家。阿卡德。科学。美国 37，205-2101。
In recent host-guest studies, the helix-forming tendencies of amino acid residues have been quantified by three groups, each obtaining similar results [Padmanabhan, S., Marqusee, S., Ridgeway, T., Laue, T. M. & Baldwin, R. L. (1990) Nature (London) 344, 268-270; O'Neil, K. T. & DeGrado, W. F. (1990) Science 250, 646-651; Lyu, P. C., Liff, M. I., Marky, L. A. & Kallenbach, N. R. (1990) Science 250, 669-673]. Here, we explore the hypothesis that these measured helix-forming propensities are due primarily to conformational restrictions imposed upon residue side chains by the helix itself. This proposition is tested by calculating the extent to which the bulky helix backbone "freezes out" available degrees of freedom in helix side chains. Specifically, for a series of apolar residues, the difference in configurational entropy, DELTA-S, between each side chain in the unfolded state and in the alpha-helical state is obtained from a simple Monte Carlo calculation. These computed entropy differences are then compared with the experimentally determined values. Measured and calculated values are found to be in close agreement for naturally occurring amino acids and in total disagreement for non-natural amino acids. In the calculation, DELTA-S(Ala) = 0. The rank order of entropy loss for the series of natural apolar side chains under consideration is Ala < Leu < Trp < Met < Phe < Ile < Tyr < Val. Among these, none favor helix formation; Ala is neutral, and all remaining residues are unfavorable to varying degrees. Thus, applied to side chains, the term "helix preference" is a misnomer. While side chain-side chain interactions may modulate stability in some instances, our results indicate that the drive to form helices must originate in the backbone, consistent with Pauling's view of four decades ago [Pauling, L., Corey, R. B. & Branson, H. R. (1951) Proc. Natl. Acad. Sci. USA 37, 205-2101.