College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
Phys Chem Chem Phys. 2019 Feb 27;21(9):5200-5214. doi: 10.1039/c8cp07859a.
Allosteric control is essential for regulating biological functions whereby stimuli such as ligand binding at one site on a protein cause a response at a distant functional site. Correlations between different sites in proteins have been used widely in identifying allosteric sites and pathways, and in designing allosteric drugs. However, the deterministic connection between correlations and allostery remains unsolved, especially considering that there are various types of correlations. Here, we combine perturbation-theory analysis and numerical calculations to study both structure- and dynamics-driven allosteric effects in an anisotropic network model (ANM). The results reveal that the allosteries are determined by the correlation (covariance) of distance fluctuations, but are irrelevant to the usual displacement correlations or time-delayed correlations. Dynamics-driven allostery is weaker than structure-driven allostery by at least one to two orders of magnitude. The intrinsic allostery capacity decays with distance by an exponential law, with the resulting characteristic distance parameter lying in the range of 7-10 Å for structure-driven allostery and 4-5 Å for dynamics-driven allostery. The importance of the cutoff distance of the ANM is also addressed.
变构控制对于调节生物功能至关重要，这种功能是通过在蛋白质的一个位点结合配体等刺激，在遥远的功能位点引起响应。在鉴定变构位点和途径以及设计变构药物方面，蛋白质中不同位点之间的相关性得到了广泛应用。然而，相关性与变构之间的确定性联系仍然没有解决，特别是考虑到存在各种类型的相关性。在这里，我们结合微扰理论分析和数值计算，在各向异性网络模型（ANM）中研究结构和动力学驱动的变构效应。结果表明，变构作用由距离波动的相关性（协方差）决定，但与通常的位移相关性或时滞相关性无关。动力学驱动的变构作用比结构驱动的变构作用至少弱一个到两个数量级。固有变构能力随距离呈指数衰减，结构驱动的变构作用的特征距离参数在 7-10Å 的范围内，动力学驱动的变构作用的特征距离参数在 4-5Å 的范围内。还讨论了 ANM 的截止距离的重要性。
