论文标题

变构和动力学校对

Allostery and Kinetic Proofreading

论文作者

Galstyan, Vahe, Phillips, Rob

论文摘要

动力学校对是中央教条及其他过程中存在的一种误差校正机制,通常需要核苷酸水解的自由能才能进行操作。尽管已知许多生物学校对方案的分子参与者,但我们对如何促进忠诚度的理解仍然不完整。在我们的工作中,我们介绍了一种替代概念方案,称为“活塞校对模型”,其中通过水解通过水解的酶激活代替了通过活塞在调节配体上执行的机械工作实现的变构激活。受Feynman的棘轮和爪网机构的启发,我们考虑了一种机械发动机,旨在驱动由降低重量驱动的活塞动作,其功能类似于细胞中ATP合酶的功能。由于其机械设计,活塞型号使我们能够调整驾驶发动机的“旋钮”,并探测速度,忠诚度和能量消散之间的分级变化和权衡。它对最佳校对所必需的条件提供了直观的解释,并揭示了变构分子通过利用可用状态的多样性来击败忠实菲尔德限制的意外能力。我们为活塞模型构建的框架也可以作为对驱动生化系统的其他研究的基础。

Kinetic proofreading is an error correction mechanism present in the processes of the central dogma and beyond, and typically requires the free energy of nucleotide hydrolysis for its operation. Though the molecular players of many biological proofreading schemes are known, our understanding of how energy consumption is managed to promote fidelity remains incomplete. In our work, we introduce an alternative conceptual scheme called 'the piston model of proofreading' where enzyme activation through hydrolysis is replaced with allosteric activation achieved through mechanical work performed by a piston on regulatory ligands. Inspired by Feynman's ratchet and pawl mechanism, we consider a mechanical engine designed to drive the piston actions powered by a lowering weight, whose function is analogous to that of ATP synthase in cells. Thanks to its mechanical design, the piston model allows us to tune the 'knobs' of the driving engine and probe the graded changes and trade-offs between speed, fidelity and energy dissipation. It provides an intuitive explanation of the conditions necessary for optimal proofreading and reveals the unexpected capability of allosteric molecules to beat the Hopfield limit of fidelity by leveraging the diversity of states available to them. The framework that we built for the piston model can also serve as a basis for additional studies of driven biochemical systems.

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