Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom.
Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045.
Proc Natl Acad Sci U S A. 2021 Apr 20;118(16). doi: 10.1073/pnas.2010057118.
Epistasis and cooperativity of folding both result from networks of energetic interactions in proteins. Epistasis results from energetic interactions among mutants, whereas cooperativity results from energetic interactions during folding that reduce the presence of intermediate states. The two concepts seem intuitively related, but it is unknown how they are related, particularly in terms of selection. To investigate their relationship, we simulated protein evolution under selection for cooperativity and separately under selection for epistasis. Strong selection for cooperativity created strong epistasis between contacts in the native structure but weakened epistasis between nonnative contacts. In contrast, selection for epistasis increased epistasis in both native and nonnative contacts and reduced cooperativity. Because epistasis can be used to predict protein structure only if it preferentially occurs in native contacts, this result indicates that selection for cooperativity may be key for predicting structure using epistasis. To evaluate this inference, we simulated the evolution of guanine nucleotide-binding protein (GB1) with and without cooperativity. With cooperativity, strong epistatic interactions clearly map out the native GB1 structure, while allowing the presence of intermediate states (low cooperativity) obscured the structure. This indicates that using epistasis measurements to reconstruct protein structure may be inappropriate for proteins with stable intermediates.
折叠的上位性和协同性都源于蛋白质中能量相互作用的网络。上位性源于突变体之间的能量相互作用，而协同性源于折叠过程中的能量相互作用，降低了中间状态的存在。这两个概念似乎直观上相关，但它们之间的关系尚不清楚，特别是在选择方面。为了研究它们的关系，我们模拟了在协同性选择下和分别在上位性选择下的蛋白质进化。强烈的协同性选择在天然结构中的接触之间产生了强烈的上位性，但削弱了非天然接触之间的上位性。相比之下，上位性选择增加了天然和非天然接触中的上位性，并降低了协同性。因为只有当上位性优先发生在天然接触中时，它才能用于预测蛋白质结构，所以这一结果表明，协同性选择可能是使用上位性预测结构的关键。为了评估这一推断，我们模拟了具有和不具有协同性的鸟嘌呤核苷酸结合蛋白（GB1）的进化。有了协同性，强烈的上位性相互作用清楚地描绘出了天然的 GB1 结构，而允许中间状态（低协同性）的存在则掩盖了结构。这表明，使用上位性测量来重建蛋白质结构可能不适合具有稳定中间态的蛋白质。
