Department of Chemistry, University of Texas at Austin, TX 78712, USA.
Department of Chemistry, University of Texas at Austin, TX 78712, USA.
Trends Biochem Sci. 2019 Aug;44(8):675-687. doi: 10.1016/j.tibs.2019.04.003. Epub 2019 May 29.
Theory and simulations predicted that the sizes of the unfolded states of globular proteins should decrease as the denaturant concentration is reduced from a high to a low value. However, small angle X-ray scattering (SAXS) data were used to assert the opposite, while interpretation of single molecule Förster resonance energy transfer experiments (FRET) supported the theoretical predictions. The disagreement between the two experiments is the SAXS-FRET controversy. By harnessing recent advances in SAXS and FRET experiments and setting these findings in the context of a general theory and simulations, which do not rely on experimental data, we establish that compaction of unfolded states under native conditions is universal. The theory also predicts that proteins rich in β-sheets are more collapsible than α-helical proteins. Because the extent of compaction is small, experiments have to be accurate and their interpretations should be as model-free as possible. Theory also suggests that collapsibility itself could be a physical restriction on the evolution of foldable sequences, and also provides a physical basis for the origin of multidomain proteins.
理论和模拟预测，球状蛋白的去折叠状态的大小应该随着变性剂浓度从高到低而减小。然而，小角度 X 射线散射（SAXS）数据却表明相反的结果，而单分子Förster 共振能量转移实验（FRET）的解释则支持理论预测。这两个实验之间的分歧就是 SAXS-FRET 争议。通过利用 SAXS 和 FRET 实验的最新进展，并将这些发现置于不依赖实验数据的一般理论和模拟的背景下，我们确定了在天然条件下去折叠状态的紧缩是普遍存在的。该理论还预测富含β-折叠的蛋白质比α-螺旋蛋白质更容易折叠。由于紧缩的程度很小，因此实验必须精确，并且它们的解释应该尽可能不依赖于模型。该理论还表明，折叠性本身可能是对可折叠序列进化的物理限制，并且为多结构域蛋白质的起源提供了物理基础。
