Tobias D J, Sneddon S F, Brooks C L
Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA 15213.
J Mol Biol. 1990 Dec 5;216(3):783-96. doi: 10.1016/0022-2836(90)90399-7.
We have carried out molecular dynamics simulations to study the conformational equilibria of two blocked dipeptides, Ac-Ala-Ala-NHMe and trans-Ac-Pro-Ala-NHMe, in water (Ac, amino-terminal blocking group COCH3; NHMe, carboxy-terminal blocking group NHCH3). Using specialized sampling techniques we computed free-energy surfaces as functions of a conformation co-ordinate that corresponds to hydrogen-bonded reverse turns at small values and to extended conformations at large values. The free-energy difference between hydrogen-bonded reverse turn conformations and extended conformations, determined from the equilibrium constants for reverse turn unfolding, is approximately -5 kcal/mole for Ac-Ala-Ala-NHMe, and -10 kcal/mole for Ac-Pro-Ala-NHMe. These results demonstrate that reverse turns in blocked dipeptides are intrinsically unstable in water. That is, in the absence of strongly stabilizing sequence-specific inter-residue interactions involving side-chains and/or charged terminal groups, the extended conformations of small peptides are highly favored in solution. By thermodynamically decomposing the free-energy differences, we found that the peptide-water entropy is the primary reason for the exceptional stability of the extended conformations of both peptides, and that the differences between the two peptides are primarily due to differences in the peptide-water interactions. In addition, we assessed the "proline effect" on the conformational equilibria by comparing the differences in configurational entropies between the reverse turn and extended conformations of the two peptides. As expected, the extended conformation of the Pro-Ala peptide is destabilized by reduced configurational entropy, but the effect is negligible in the blocked dipeptides. Finally, we compared our results with the results of several other experimental studies to identify some of the specific interactions that may be responsible for stabilizing reverse turns in small peptides in solution.
我们进行了分子动力学模拟，以研究两种封闭二肽Ac-Ala-Ala-NHMe和反式-Ac-Pro-Ala-NHMe在水中的构象平衡（Ac，氨基末端封闭基团COCH3；NHMe，羧基末端封闭基团NHCH3）。使用专门的采样技术，我们计算了自由能表面，它是一个构象坐标的函数，该坐标在小值时对应于氢键反向转角，在大值时对应于伸展构象。根据反向转角解折叠的平衡常数确定，氢键反向转角构象和伸展构象之间的自由能差，对于Ac-Ala-Ala-NHMe约为-5千卡/摩尔，对于Ac-Pro-Ala-NHMe约为-10千卡/摩尔。这些结果表明，封闭二肽中的反向转角在水中本质上是不稳定的。也就是说，在不存在涉及侧链和/或带电末端基团的强稳定序列特异性残基间相互作用的情况下，小肽的伸展构象在溶液中非常有利。通过对自由能差进行热力学分解，我们发现肽-水熵是两种肽伸展构象异常稳定的主要原因，并且两种肽之间的差异主要是由于肽-水相互作用的差异。此外，我们通过比较两种肽反向转角和伸展构象之间构型熵的差异，评估了“脯氨酸效应”对构象平衡的影响。正如预期的那样，Pro-Ala肽伸展构象因构型熵降低而不稳定，但在封闭二肽中这种影响可以忽略不计。最后，我们将我们的结果与其他几项实验研究的结果进行比较，以确定一些可能负责稳定溶液中小肽反向转角的特定相互作用。
