State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
PLoS One. 2010 Nov 4;5(11):e15375. doi: 10.1371/journal.pone.0015375.
Proteins function by interacting with other molecules, where both native and nonnative interactions play important roles. Native interactions contribute to the stability and specificity of a complex, whereas nonnative interactions mainly perturb the binding kinetics. For intrinsically disordered proteins (IDPs), which do not adopt rigid structures when being free in solution, the role of nonnative interactions may be more prominent in binding processes due to their high flexibilities. In this work, we investigated the effect of nonnative hydrophobic interactions on the coupled folding and binding processes of IDPs and its interplay with chain flexibility by conducting molecular dynamics simulations. Our results showed that the free-energy profiles became rugged, and intermediate states occurred when nonnative hydrophobic interactions were introduced. The binding rate was initially accelerated and subsequently dramatically decreased as the strength of the nonnative hydrophobic interactions increased. Both thermodynamic and kinetic analysis showed that disordered systems were more readily affected by nonnative interactions than ordered systems. Furthermore, it was demonstrated that the kinetic advantage of IDPs ("fly-casting" mechanism) was enhanced by nonnative hydrophobic interactions. The relationship between chain flexibility and protein aggregation is also discussed.
蛋白质通过与其他分子相互作用发挥功能，其中天然相互作用和非天然相互作用都起着重要作用。天然相互作用有助于复合物的稳定性和特异性，而非天然相互作用主要干扰结合动力学。对于在溶液中自由时不采取刚性结构的无规卷曲蛋白质 (IDPs)，由于其高度的灵活性，非天然相互作用在结合过程中可能更为突出。在这项工作中，我们通过分子动力学模拟研究了非天然疏水相互作用对 IDPs 的折叠和结合过程的影响及其与链柔性的相互作用。研究结果表明，当引入非天然疏水相互作用时，自由能曲线变得崎岖不平，中间状态出现。随着非天然疏水相互作用强度的增加，结合速率最初会加速，随后会急剧下降。热力学和动力学分析均表明，无序系统比有序系统更容易受到非天然相互作用的影响。此外，还证明了非天然疏水相互作用增强了 IDPs 的动力学优势（“飞抛”机制）。还讨论了链柔性与蛋白质聚集之间的关系。
