Understanding how changes in amino acid sequence alter protein dynamics and allosteric signaling would illuminate strategies for protein design. To gain insight into this process, we have combined molecular dynamics simulations with ancestral sequence reconstruction to explore conformational dynamics in two ancient steroid receptors (SRs) to determine how allosteric signaling pathways were altered over evolution to generate hormone specificity. In a broad panel of aromatized and non-aromatized hormones, we investigate inter-residue contacts that facilitate allosteric signaling. This work reveals interhelical interactions that act as ligand sensors and explain the structural and dynamical basis for ligand discrimination in SRs. These sensors are part of a conserved SR allosteric network and persist over long simulation time scales, indicating that evolutionary substitutions rewire ancient SR networks to achieve functional evolution. This powerful combination of computation, ancestral reconstruction, and biochemistry may illuminate allosteric mechanisms and functional evolution in other protein families.

中文翻译：

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重新布线古代残基相互作用网络推动了类固醇受体特异性的发展。

了解氨基酸序列的变化如何改变蛋白质动力学和变构信号将阐明蛋白质设计的策略。为了深入了解这一过程，我们将分子动力学模拟与祖先序列重建相结合，以探索两种古老的类固醇受体（SR）的构象动力学，以确定在进化过程中变构信号通路如何改变以产生激素特异性。在广泛的芳香化和非芳香化激素中，我们研究了促进变构信号的残基间接触。这项工作揭示了充当配体传感器的螺旋间相互作用，并解释了SR中配体识别的结构和动力学基础。这些传感器是保守的SR变构网络的一部分，并且可以在较长的仿真时间内保持不变，这表明进化替代可以重新连接古代SR网络以实现功能进化。计算，祖先重建和生物化学的强大结合可能阐明了其他蛋白质家族的变构机制和功能进化。