蛋白质变构模型中稀疏性和模块性的演化
Evolution of sparsity and modularity in a model of protein allostery
摘要：
蛋白质的序列不仅受到当前选择下的物理和生化性质的限制，而且还受到其过去进化历史的特征的限制。理解这些进化限制的程度和形式对于解释蛋白质序列中的信息是很重要的。为了研究这个问题，我们引入了一个简单但物理的蛋白质进化模型，其中选择目标是变构，即蛋白质表面远端位点的功能耦合。该模型显示了蛋白质结构内氨基酸之间的偶联的几何组织如何关键地取决于其进化历史。特别是，两种情况下被发现产生的功能约束的空间集中：高突变率和波动的选择压力。这第二种情况提供了一个合理的解释天然蛋白质的高耐受性突变和空间组织的最不容忍的氨基酸，揭示了序列分析和诱变实验。它还意味着一种适应新的选择压力的能力，这种能力与观察一致。此外，该模型说明了几个独立的功能模块可能会出现在同一个蛋白质结构，这取决于过去的环境波动的性质。因此，我们的模型涉及蛋白质的进化历史和进化潜力的几何形状的功能限制，与解码和工程蛋白质序列的影响。
英文摘要：
The sequence of a protein is not only constrained by its physical and biochemical properties under current selection, but also by features of its past evolutionary history. Understanding the extent and the form that these evolutionary constraints may take is important to interpret the information in protein sequences. To study this problem, we introduce a simple but physical model of protein evolution where selection targets allostery, the functional coupling of distal sites on protein surfaces. This model shows how the geometrical organization of couplings between amino acids within a protein structure can depend crucially on its evolutionary history. In particular, two scenarios are found to generate a spatial concentration of functional constraints: high mutation rates and fluctuating selective pressures. This second scenario offers a plausible explanation for the high tolerance of natural proteins to mutations and for the spatial organization of their least tolerant amino acids, as revealed by sequence analyses and mutagenesis experiments. It also implies a faculty to adapt to new selective pressures that is consistent with observations. Besides, the model illustrates how several independent functional modules may emerge within a same protein structure, depending on the nature of past environmental fluctuations. Our model thus relates the evolutionary history and evolutionary potential of proteins to the geometry of their functional constraints, with implications for decoding and engineering protein sequences.
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