Kannan Adithi, Naganathan Athi N
Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India.
iScience. 2022 Sep 22;25(10):105181. doi: 10.1016/j.isci.2022.105181. eCollection 2022 Oct 21.
Mutational effects in globular proteins exhibit an exponential-like decreasing dependence on distance from the mutated site, suggestive of long-range modulation of structural-thermodynamic features. Here, we extract the physical origins of this pattern by employing a statistical-mechanical model to construct conformational ensembles of three archetypal proteins. Through large-scale alanine-scanning mutagenesis, we show that inter-residue differential coupling free energies, which are characteristic ensemble thermodynamic properties, follow a similar exponential distance dependence with the effects felt until ∼15-20 Å from the mutated site. From the perspective of an ensemble-averaged structure, this feature arises via long-range reorganization of the interaction network on mutations which is more significant for charged residues compared to hydrophobic residues. Our work highlights how subtle alterations in the microscopic distribution of states manifest as a macroscopic distance dependence, the physical origins of mutation-induced dynamic allostery, and the necessity to consider the global intra-protein interaction network to understand mutational outcomes.
球状蛋白中的突变效应呈现出一种与距突变位点的距离呈指数式下降的依赖性，这暗示了结构热力学特征的远程调节。在此，我们通过采用统计力学模型构建三种典型蛋白质的构象集合来提取这种模式的物理根源。通过大规模丙氨酸扫描诱变，我们表明，作为集合热力学特性的残基间差异耦合自由能，遵循类似的指数距离依赖性，其影响可延伸至距突变位点约15 - 20埃处。从集合平均结构的角度来看，这一特征源于突变时相互作用网络的远程重组，与疏水残基相比，带电残基的这种重组更为显著。我们的工作突出了微观状态分布的细微变化如何表现为宏观距离依赖性、突变诱导的动态变构的物理根源，以及考虑蛋白质内部全局相互作用网络以理解突变结果的必要性。
