Chong Song-Ho, Ham Sihyun
Department of Chemistry, The Research Institute of Natural Sciences, Sookmyung Women's University Cheongpa-ro-47-gil 100, Yongsan-ku Seoul 04310 Korea
Chem Sci. 2021 Mar 24;12(16):5944-5951. doi: 10.1039/d0sc07025d. eCollection 2021 Apr 28.
Cooperativity is considered to be a key organizing principle behind biomolecular assembly, recognition and folding. However, it has remained very challenging to quantitatively characterize how cooperative processes occur on a concerted, multiple-interaction basis. Here, we address how and when the folding process is cooperative on a molecular scale. To this end, we analyze multipoint time-correlation functions probing time-dependent communication between multiple amino acids, which were computed from long folding simulation trajectories. We find that the simultaneous multiple amino-acid contact formation, which is absent in the unfolded state, starts to develop only upon entering the folding transition path. Interestingly, the transition state, whose presence is connected to the macrostate cooperative behavior known as the two-state folding, can be identified as the state in which the amino-acid cooperativity is maximal. Thus, our work not only provides a new mechanistic view on how protein folding proceeds on a multiple-interaction basis, but also offers a conceptually novel characterization of the folding transition state and the molecular origin of the phenomenological cooperative folding behavior. Moreover, the multipoint correlation function approach adopted here is general and can be used to expand the understanding of cooperative processes in complex chemical and biomolecular systems.
协同性被认为是生物分子组装、识别和折叠背后的关键组织原则。然而，要定量表征协同过程是如何在协同的、多相互作用基础上发生的，仍然极具挑战性。在此，我们探讨折叠过程在分子尺度上如何以及何时具有协同性。为此，我们分析了多点时间关联函数，该函数探测多个氨基酸之间随时间变化的通信，这些函数是根据长折叠模拟轨迹计算得出的。我们发现，在未折叠状态中不存在的同时多个氨基酸接触的形成，仅在进入折叠过渡路径时才开始发展。有趣的是，过渡态的存在与被称为两态折叠的宏观态协同行为相关，它可被确定为氨基酸协同性最大的状态。因此，我们的工作不仅为蛋白质折叠如何在多相互作用基础上进行提供了新的机制观点，还为折叠过渡态以及现象学协同折叠行为的分子起源提供了概念上新颖的表征。此外，这里采用的多点关联函数方法具有通用性，可用于拓展对复杂化学和生物分子系统中协同过程的理解。
