Arantes Pablo R, Patel Amun C, Palermo Giulia
Department of Bioengineering, University of California Riverside, 900 University Avenue, Riverside, CA 52512, United States; Department of Chemistry, University of California Riverside, 900 University Avenue, Riverside, CA 52512, United States. Electronic address: https://twitter.com/pablitoarantes.
Department of Bioengineering, University of California Riverside, 900 University Avenue, Riverside, CA 52512, United States; Department of Chemistry, University of California Riverside, 900 University Avenue, Riverside, CA 52512, United States.
J Mol Biol. 2022 Sep 15;434(17):167518. doi: 10.1016/j.jmb.2022.167518. Epub 2022 Feb 28.
Many large protein-nucleic acid complexes exhibit allosteric regulation. In these systems, the propagation of the allosteric signaling is strongly coupled to conformational dynamics and catalytic function, challenging state-of-the-art analytical methods. Here, we review established and innovative approaches used to elucidate allosteric mechanisms in these complexes. Specifically, we report network models derived from graph theory and centrality analyses in combination with molecular dynamics (MD) simulations, introducing novel schemes that implement the synergistic use of graph theory with enhanced simulations methods and ab-initio MD. Accelerated MD simulations are used to construct "enhanced network models", describing the allosteric response over long timescales and capturing the relation between allostery and conformational changes. "Ab-initio network models" combine graph theory with ab-initio MD and quantum mechanics/molecular mechanics (QM/MM) simulations to describe the allosteric regulation of catalysis by following the step-by-step dynamics of biochemical reactions. This approach characterizes how the allosteric regulation changes from reactants to products and how it affects the transition state, revealing a tense-to-relaxed allosteric regulation along the chemical step. Allosteric models and applications are showcased for three paradigmatic examples of allostery in protein-nucleic acid complexes: (i) the nucleosome core particle, (ii) the CRISPR-Cas9 genome editing system and (iii) the spliceosome. These methods and applications create innovative protocols to determine allosteric mechanisms in protein-nucleic acid complexes that show tremendous promise for medicine and bioengineering.
许多大型蛋白质 - 核酸复合物表现出变构调节。在这些系统中，变构信号的传播与构象动力学和催化功能紧密耦合，这对现有最先进的分析方法提出了挑战。在这里，我们综述了用于阐明这些复合物中变构机制的既定方法和创新方法。具体而言，我们报告了源自图论和中心性分析并结合分子动力学（MD）模拟的网络模型，引入了将图论与增强模拟方法和从头算MD协同使用的新方案。加速MD模拟用于构建“增强网络模型”，描述长时间尺度上的变构响应并捕捉变构与构象变化之间的关系。“从头算网络模型”将图论与从头算MD和量子力学/分子力学（QM/MM）模拟相结合，通过跟踪生化反应的逐步动力学来描述催化的变构调节。这种方法表征了变构调节如何从反应物转变为产物以及它如何影响过渡态，揭示了沿化学步骤从紧张到松弛的变构调节。针对蛋白质 - 核酸复合物中变构的三个典型例子展示了变构模型及其应用：（i）核小体核心颗粒，（ii）CRISPR - Cas9基因组编辑系统，以及（iii）剪接体。这些方法和应用创建了创新方案来确定蛋白质 - 核酸复合物中的变构机制，这对医学和生物工程具有巨大的前景。
