Chhajer M, Crippen G M
Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599 U.S.A.
J Biol Phys. 2004 Jun;30(2):171-85. doi: 10.1023/B:JOBP.0000035854.68334.dd.
Empirical protein folding potentialfunctions should have a global minimum nearthe native conformationof globular proteins that fold stably, andthey should give the correct free energy offolding. We demonstrate that otherwise verysuccessful potentials fail to have even alocal minimumanywhere near the native conformation, anda seemingly well validated method ofestimatingthe thermodynamic stability of the nativestate is extremely sensitive to smallperturbations inatomic coordinates. These are bothindicative of fitting a great deal ofirrelevant detail. Here weshow how to devise a robust potentialfunction that succeeds very well at bothtasks, at least for alimited set of proteins, and this involvesdeveloping a novel representation of thedenatured state.Predicted free energies of unfolding for 25mutants of barnase are in close agreementwith theexperimental values, while for 17 mutantsthere are substantial discrepancies.
经验性蛋白质折叠势函数应在稳定折叠的球状蛋白质的天然构象附近有一个全局最小值，并且它们应给出正确的折叠自由能。我们证明，否则非常成功的势函数甚至在天然构象附近的任何地方都没有局部最小值，并且一种看似经过充分验证的估计天然态热力学稳定性的方法对原子坐标的微小扰动极其敏感。这些都表明拟合了大量不相关的细节。在这里，我们展示了如何设计一种强大的势函数，该势函数在这两个任务上都非常成功，至少对于一组有限的蛋白质是这样，这涉及开发一种变性态的新表示。针对25个巴纳酶突变体预测的解折叠自由能与实验值密切吻合，而对于17个突变体则存在显著差异。
