Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
Paulson School of Engineering and Applied Science, Harvard University, Cambridge, MA 02138.
Proc Natl Acad Sci U S A. 2022 Aug 2;119(31):e2109718119. doi: 10.1073/pnas.2109718119. Epub 2022 Jul 28.
Primary nucleation is the fundamental event that initiates the conversion of proteins from their normal physiological forms into pathological amyloid aggregates associated with the onset and development of disorders including systemic amyloidosis, as well as the neurodegenerative conditions Alzheimer's and Parkinson's diseases. It has become apparent that the presence of surfaces can dramatically modulate nucleation. However, the underlying physicochemical parameters governing this process have been challenging to elucidate, with interfaces in some cases having been found to accelerate aggregation, while in others they can inhibit the kinetics of this process. Here we show through kinetic analysis that for three different fibril-forming proteins, interfaces affect the aggregation reaction mainly through modulating the primary nucleation step. Moreover, we show through direct measurements of the Gibbs free energy of adsorption, combined with theory and coarse-grained computer simulations, that overall nucleation rates are suppressed at high and at low surface interaction strengths but significantly enhanced at intermediate strengths, and we verify these regimes experimentally. Taken together, these results provide a quantitative description of the fundamental process which triggers amyloid formation and shed light on the key factors that control this process.
一级成核是引发蛋白质从正常生理形态向与包括系统性淀粉样变性、阿尔茨海默病和帕金森病等神经退行性疾病的发病和发展相关的病理淀粉样聚集物转变的基本事件。显然，表面的存在可以显著调节成核。然而，控制这一过程的潜在物理化学参数一直难以阐明，在某些情况下，界面会加速聚集，而在其他情况下，它们可以抑制这一过程的动力学。在这里，我们通过动力学分析表明，对于三种不同的纤维状蛋白，界面主要通过调节一级成核步骤来影响聚集反应。此外，我们通过直接测量吸附的吉布斯自由能，结合理论和粗粒度计算机模拟，表明在高和低表面相互作用强度下，整体成核速率受到抑制，但在中等强度下显著增强，我们通过实验验证了这些区域。总之，这些结果提供了对触发淀粉样形成的基本过程的定量描述，并揭示了控制这一过程的关键因素。
