Institute of High Performance Computing, Agency for Science, Technology and Research , 1 Fusionopolis Way, #16-16, Connexis , Singapore 138632 , Republic of Singapore.
Institute of Chemical and Engineering Sciences, Agency for Science, Technology and Research , 1 Pesek Road , Jurong Island, Singapore 627833 , Republic of Singapore.
J Phys Chem B. 2018 Oct 4;122(39):9274-9288. doi: 10.1021/acs.jpcb.8b06452. Epub 2018 Sep 19.
The stability of two small proteins, one composed of three α-helices (α-peptide) and another composed of a β-sheet (β-peptide) solvated in five different ionic liquids (ILs), is analyzed using replica exchange molecular dynamics (REMD) simulations. ILs are composed of 1-butyl-3-methylimidazolium (BMIM) cations, paired with five different anions of varying hydrophilicity and size, namely, Cl, NO, BF, PF, and NTf. REMD simulations greatly improve structure sampling and mitigate bias toward the initial folded peptide structure, thereby providing more adequate simulations to study protein stability. Cluster analysis, DSSP analysis and derivation of radius of gyration, interaction energies, and hydrogen bonding are used to quantify structural peptide changes in a large temperature range from 250 to 650 K. α-Peptides are least stable in ILs that contain small anions with localized negative charge, such as in BMIM-Cl and BMIM-NO. Destabilization is caused by direct electrostatic interactions of anions with α-helices that are exposed to the solvent. This destabilization is characterized not by unfolded but instead by compact misfolded structures. Also, β-peptides retain compact structures up to at least 400 K, below which unfolding hardly occurs. However, intrapeptide hydrogen bonds that constitute the β-sheet are not exposed to the solvent. Therefore, β-peptides are generally more stable than α-peptides in all considered ILs. Moreover, on contrary to α-peptides, β-peptides are least stable in less polar ILs, such as BMIM-PF and BMIM-NTf, because dissolving β-sheets requires large structural changes of the peptide. Such transitions are energetically less opposed in ILs with weaker mutual ion coordination. A large interaction density within ILs, for example, in BMIM-Cl, is thus kinetically trapping β-peptides in the original folded state. Additionally, in BMIM-BF, interactions with β-peptides are so weak, compared to an aqueous solvent, resulting in stronger interactions within the peptide, which extend β-sheets, hence causing misfolding of a different kind. The results reveal how direct ion-peptide interactions and solvent reorganization energy in ILs are both crucial in determining protein stability. These insights could translate into guidelines for the design of new IL solvents with improved protein stability.
两种小蛋白的稳定性，一种由三个α-螺旋（α-肽）组成，另一种由β-折叠（β-肽）组成，分别在五种不同的离子液体（ILs）中溶解，使用复制交换分子动力学（REMD）模拟进行分析。ILs由 1-丁基-3-甲基咪唑鎓（BMIM）阳离子组成，与五种不同的亲水性和尺寸的阴离子配对，分别为 Cl、NO、BF、PF 和 NTf。REMD 模拟大大提高了结构采样，减轻了对初始折叠肽结构的偏见，从而提供了更充分的模拟来研究蛋白质稳定性。使用聚类分析、DSSP 分析和回转半径、相互作用能和氢键的推导，在 250 到 650 K 的大温度范围内量化了肽结构的变化。在含有局部负电荷的小阴离子的 ILs 中，α-肽最不稳定，例如在 BMIM-Cl 和 BMIM-NO 中。这种不稳定是由暴露在溶剂中的阴离子与α-螺旋的直接静电相互作用引起的。这种不稳定的特征不是无规卷曲，而是紧凑的错误折叠结构。此外，β-肽在至少 400 K 以下仍保持紧凑的结构，在该温度以下几乎不会展开。然而，构成β-折叠的肽内氢键并不暴露在溶剂中。因此，β-肽在所有考虑的 ILs 中通常比α-肽更稳定。此外，与α-肽相反，β-肽在极性较小的 ILs 中最不稳定，例如 BMIM-PF 和 BMIM-NTf，因为溶解β-折叠需要肽的大结构变化。在相互离子配位较弱的 ILs 中，这种转变在能量上受到的阻碍较小。因此，在 ILs 中具有较大的相互作用密度，例如在 BMIM-Cl 中，动力学上会将β-肽困在原始折叠状态。此外，在 BMIM-BF 中，与β-肽的相互作用与水溶剂相比非常弱，导致肽内的相互作用更强，从而延伸β-折叠，从而导致不同类型的错误折叠。结果揭示了直接的离子-肽相互作用和 IL 中溶剂重组能如何共同决定蛋白质的稳定性。这些见解可以转化为设计具有改进的蛋白质稳定性的新型 IL 溶剂的指南。
