DNA聚合酶的校正：一个新的具有高阶末端效应的动力学模型
Proofreading of DNA Polymerase: a new kinetic model with higher-order terminal effects
摘要：
DNA聚合酶（DNAP）复制DNA的保真度一直是生物学中的一个重要问题。虽然大量的实验已经揭示了DNAP的分子结构和工作机制的细节，DNAP由聚合酶位点和核酸外切酶（校对）位点组成，但对保真度问题的理论研究却很少。第一个明确考虑这两个地点的模型是在20世纪70年代提出的，其基本思想被后来的模型广泛接受。然而，所有这些模型都没有系统和严格地研究DNAP保真度的主导因素，即聚合途径和校对途径协调以实现高保真度的高阶末端效应。在本文中，我们提出了一个新的和全面的动力学模型DNAP的基础上，最近的一些实验观察，其中包括以前的模型作为特例。我们提出了一个严格的和统一的处理相应的稳态动力学方程的任何顺序的终端效应，并推导出分析表达式的保真度在生物相关条件下的动力学参数。这些表达式提供了关于高阶末端效应如何以逐阶方式对保真度做出重大贡献的新见解，并且还表明聚合和校对机制仅由很少的关键参数主导。然后，我们应用这些结果来计算一些真正的DNAP的保真度，这是在很好的协议与以前的直观估计实验者。
英文摘要：
The fidelity of DNA replication by DNA polymerase (DNAP) has long been an important issue in biology. While numerous experiments have revealed details of the molecular structure and working mechanism of DNAP which consists of both a polymerase site and an exonuclease (proofreading) site, there were quite few theoretical studies on the fidelity issue. The first model which explicitly considered both sites was proposed in 1970s' and the basic idea was widely accepted by later models. However, all these models did not systematically and rigorously investigate the dominant factor on DNAP fidelity, i.e, the higher-order terminal effects through which the polymerization pathway and the proofreading pathway coordinate to achieve high fidelity. In this paper, we propose a new and comprehensive kinetic model of DNAP based on some recent experimental observations, which includes previous models as special cases. We present a rigorous and unified treatment of the corresponding steady-state kinetic equations of any-order terminal effects, and derive analytical expressions for fidelity in terms of kinetic parameters under bio-relevant conditions. These expressions offer new insights on how the the higher-order terminal effects contribute substantially to the fidelity in an order-by-order way, and also show that the polymerization-and-proofreading mechanism is dominated only by very few key parameters. We then apply these results to calculate the fidelity of some real DNAPs, which are in good agreements with previous intuitive estimates given by experimentalists.
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