Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden.
Biophys J. 2012 Feb 8;102(3):569-78. doi: 10.1016/j.bpj.2011.12.008. Epub 2012 Feb 7.
Coupled folding-binding is central to the function of many intrinsically disordered proteins, yet not fully understood. With a continuous three-letter protein model, we explore the free-energy landscape of pairs of interacting sequences and how it is impacted by 1), variations in the binding mechanism; and 2), the addition of disordered flanks to the binding region. In particular, we focus on two sequences, one with 16 and one with 35 amino acids, which make a stable dimeric three-helix bundle at low temperatures. Three distinct binding mechanisms are realized by altering the stabilities of the individual monomers: docking, coupled folding-binding of a single α-helix, and synergistic folding and binding. Compared to docking, the free-energy barrier for binding is reduced when the single α-helix is allowed to fold upon binding, but only marginally. A greater reduction is found for synergistic folding, which in addition results in a binding transition state characterized by very few interchain contacts. Disordered flanking chain segments attached to the α-helix sequence can, despite a negligible impact on the dimer stability, lead to a downhill free-energy surface in which the barrier for binding is eliminated.
偶联折叠结合是许多无规卷曲蛋白质功能的核心，但尚未完全理解。我们使用连续的三字母蛋白质模型，探索了相互作用序列对的自由能景观，以及它如何受到以下因素的影响：1）结合机制的变化；2）结合区域无序侧翼的添加。特别地，我们关注两个序列，一个序列有 16 个氨基酸，另一个序列有 35 个氨基酸，它们在低温下形成稳定的三聚体三螺旋束。通过改变单体的稳定性，可以实现三种不同的结合机制：对接、单个α-螺旋的偶联折叠结合，以及协同折叠和结合。与对接相比，当允许单个α-螺旋在结合时折叠时，结合的自由能障碍会降低，但仅略有降低。协同折叠的降低幅度更大，此外还导致结合过渡态的特征是很少有链间接触。尽管无序侧翼链段对二聚体稳定性的影响可以忽略不计，但它可以导致结合的自由能表面呈下坡状，其中结合的障碍被消除。
