On the Protein Folding Problem

蛋白质是在活细胞中执行重要功能的生物主力。在它们能够执行所需的功能之前，蛋白质必须折叠成复杂的三维结构，但执行这种折叠过程的潜在因素尚不清楚。虽然导致蛋白质折叠的步骤是快速和高效的，但有时会出错。这可能会产生有害的后果，因为蛋白质的不正确折叠被认为是许多疾病的原因，如阿尔茨海默病和某些类型的癌症。我们建议在这里建立一个仪器，将使在一个非常广泛的时间范围内的蛋白质折叠动力学的系统研究。新仪器的一个关键特征将包括一个高压单元，它允许通过不同的摩擦力来控制构象运动。该仪器将用于跟踪由二硫键断裂引发的短蛋白的大规模展开。这项研究将揭示与展开和再折叠过程相关的机制和热力学。后续的工作应该有助于揭示金属离子在促进阿尔茨海默病中的作用。

Proteins are the biological workhorses that carry out vital functions in living cells. Before they can carry out their required functions, the proteins must fold into a complex three-dimensional structure but the underlying factors that perform this folding process remain unclear. Although the steps leading to protein folding are fast and highly efficient, things sometimes go wrong. This can have harmful consequences, as the incorrect folding of proteins is thought to be the cause of many diseases, such as Alzheimer's disease and certain types of cancer. We propose here to build an instrument that will enable the systematic study of the dynamics of protein folding over a very wide temporal range. A key feature of the new instrument will involve a high-pressure cell that allows conformational motion to be controlled by varying frictional forces. The instrument will be used to follow large-scale unfolding of a short protein triggered by breaking a disulphide bond. This study should expose the mechanism and thermodynamics associated with the unfolding and refolding processes. Subsequent work should help unravel the role of metal ions in promoting Alzheimer's disease.