Dubrow Alyssa, Kim Iktae, Topo Elias, Cho Jae-Hyun
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, United States.
Front Mol Biosci. 2021 Jul 8;8:716477. doi: 10.3389/fmolb.2021.716477. eCollection 2021.
Biomolecular recognition often involves conformational changes as a prerequisite for binding (i.e., conformational selection) or concurrently with binding (i.e., induced-fit). Recent advances in structural and kinetic approaches have enabled the detailed characterization of protein motions at atomic resolution. However, to fully understand the role of the conformational dynamics in molecular recognition, studies on the binding transition state are needed. Here, we investigate the binding transition state between nonstructural protein 1 (NS1) of the pandemic 1918 influenza A virus and the human p85β subunit of PI3K. 1918 NS1 binds to p85β conformational selection. We present the free-energy mapping of the transition and bound states of the 1918 NS1:p85β interaction using linear free energy relationship and ϕ-value analyses. We find that the binding transition state of 1918 NS1 and p85β is structurally similar to the bound state with well-defined binding orientation and hydrophobic interactions. Our finding provides a detailed view of how protein motion contributes to the development of intermolecular interactions along the binding reaction coordinate.
生物分子识别通常涉及构象变化，这是结合的先决条件（即构象选择）或与结合同时发生（即诱导契合）。结构和动力学方法的最新进展使得能够在原子分辨率下详细表征蛋白质运动。然而，为了全面理解构象动力学在分子识别中的作用，需要对结合过渡态进行研究。在这里，我们研究了1918年大流行甲型流感病毒的非结构蛋白1（NS1）与PI3K的人类p85β亚基之间的结合过渡态。1918 NS1通过构象选择与p85β结合。我们使用线性自由能关系和ϕ值分析展示了1918 NS1:p85β相互作用的过渡态和结合态的自由能图谱。我们发现1918 NS1和p85β的结合过渡态在结构上与具有明确结合取向和疏水相互作用的结合态相似。我们的发现提供了一个关于蛋白质运动如何沿着结合反应坐标促进分子间相互作用发展的详细视角。
