Sealy Center for Structural Biology and Molecular Biophysics, Departments of Biochemistry and Molecular Biology and Pharmacology and Toxicology, University of Texas Medical Branch , 301 University Blvd, Galveston, Texas 77555-0304, United States.
J Phys Chem B. 2013 Dec 27;117(51):16428-35. doi: 10.1021/jp409693p. Epub 2013 Dec 13.
The electrostatic (ΔGel), van der Waals cavity-formation (ΔGvdw), and total (ΔG) solvation free energies for 10 alanine peptides ranging in length (n) from 1 to 10 monomers were calculated. The free energies were computed both with fixed, extended conformations of the peptides and again for some of the peptides without constraints. The solvation free energies, ΔGel, and components ΔGvdw, and ΔG, were found to be linear in n, with the slopes of the best-fit lines being γel, γvdw, and γ, respectively. Both γel and γ were negative for fixed and flexible peptides, and γvdw was negative for fixed peptides. That γvdw was negative was surprising, as experimental data on alkanes, theoretical models, and MD computations on small molecules and model systems generally suggest that γvdw should be positive. A negative γvdw seemingly contradicts the notion that ΔGvdw drives the initial collapse of the protein when it folds by favoring conformations with small surface areas. When we computed ΔGvdw for the flexible peptides, thereby allowing the peptides to assume natural ensembles of more compact conformations, γvdw was positive. Because most proteins do not assume extended conformations, a ΔGvdw that increases with increasing surface area may be typical for globular proteins. An alternative hypothesis is that the collapse is driven by intramolecular interactions. We find few intramolecular H-bonds but show that the intramolecular van der Waals interaction energy is more favorable for the flexible than for the extended peptides, seemingly favoring this hypothesis. The large fluctuations in the vdw energy may make attributing the collapse of the peptide to this intramolecular energy difficult.
计算了 10 种长度（n）从 1 到 10 个单体的丙氨酸肽的静电（ΔGel）、范德华腔形成（ΔGvdw）和总（ΔG）溶剂化自由能。对于一些没有约束的肽，我们不仅计算了固定的、扩展的肽构象的自由能，还计算了没有约束的一些肽的自由能。发现溶剂化自由能 ΔGel 及其组成部分 ΔGvdw 和 ΔG 与 n 呈线性关系，最佳拟合线的斜率分别为 γel、γvdw 和 γ。对于固定和灵活的肽，γel 和 γ 都是负的，而对于固定的肽，γvdw 是负的。γvdw 是负的这一事实令人惊讶，因为烷烃的实验数据、理论模型以及小分子和模型系统的 MD 计算通常表明 γvdw 应该是正的。负的 γvdw 似乎与这样一种观点相矛盾，即当蛋白质折叠时，ΔGvdw 通过有利于具有小表面积的构象来驱动蛋白质的初始折叠。当我们为灵活的肽计算 ΔGvdw 时，从而允许肽采用更紧凑构象的自然集合，γvdw 是正的。由于大多数蛋白质不采用扩展构象，因此随着表面积的增加而增加的 ΔGvdw 可能是球状蛋白的典型特征。另一种假设是折叠是由分子内相互作用驱动的。我们发现很少有分子内氢键，但表明分子内范德华相互作用能对于灵活的肽比对扩展的肽更有利，似乎支持了这一假设。范德华能的大波动可能使得将肽的折叠归因于这种分子内能变得困难。
