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PNAS:计算生物学所泛素多聚体折叠中间体性质合作研究获进展

来源:中国科学院上海生命科学研究院 2011-04-18 13:54

利用机械力使蛋白质去折叠再诱导其折叠,特别适合用来研究蛋白质在外力作用下的折叠过程。这种方法被广泛应用于原子力显微镜实验(AFM)中对单个生物分子折叠机理的研究。最近,新的原子力显微镜实验发现泛素多聚体在外力去折叠后,重折叠的过程中存在大量的稳定的中间体。这些中间体在外力作用下将产生2~30纳米的距离分布,而典型的泛素单体只给出20纳米的距离分布。

中科院上海生命科学研究院计算生物学所研究组长Frauke Graeter博士和夏飞博士利用分子模拟的方法,理论研究了泛素多聚体折叠过程以及中间体的性质,并提出多聚体中单体间的相互作用将导致中间体的产生,而这些稳定的中间体通过两个相邻单体间交换相同的二级结构形成。理论计算的结果表明,去折叠后,这些中间体将产生2到30纳米的距离分布,这与实验观测的结果一致,进一步的动力学分析也与实验相符。该理论研究为泛素多聚体在外力作用下的折叠中间体提供了新的理论解释。

该研究是与美国马里兰大学的Dave Thirumalai教授合作完成,并于4月11日在线发表于美国《国家科学院院刊》(PNAS)。

该工作得到了美国健康研究所、中国国家自然科学基金、计算所奇拉实验室以及德国学术交流中心的支持。(生物谷Bioon.com)

生物谷推荐原文出处:

PNAS   doi: 10.1073/pnas.1018177108

Minimum energy compact structures in force-quench polyubiquitin folding are domain swapped

Fei Xiaa,b, D. Thirumalaic,1, and Frauke Gr?tera,b,1

Single molecule experiments that initiate folding using mechanical force are uniquely suited to reveal the nature of populated states in the folding process. Using a strategy proposed on theoretical grounds, which calls for repeated cycling of force from high to low values using force pulses, it was demonstrated in atomic force spectroscopy (AFM) experiments that an ensemble of minimum energy compact structures (MECS) are sampled during the folding of polyubiquitin. The structures in the ensemble are mechanically resistant to a lesser extent than the native state. Remarkably, forced unfolding of the populated intermediates reveals a broad distribution of extensions including steps up to 30 nm and beyond. We show using molecular simulations that favorable interdomain interactions leading to domain swapping between adjacent ubiquitin modules results in the formation of the ensemble of MECS, whose unfolding leads to an unusually broad distribution of steps. We obtained the domain-swapped structures using coarse-grained ubiquitin dimer models by exchanging native interactions between two monomeric ubiquitin molecules. Brownian dynamics force unfolding of the proposed domain-swapped structures, with mechanical stability that is approximately 100-fold lower than the native state, gives rise to a distribution of extensions from 2 to 30 nm. Our results, which are in quantitative agreement with AFM experiments, suggest that domain swapping may be a general mechanism in the assembly of multi-sub-unit proteins.

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