Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey.
Department of Chemistry, Princeton University, Princeton, New Jersey.
Proteins. 2019 Jul;87(7):569-578. doi: 10.1002/prot.25680. Epub 2019 Mar 18.
We study computationally a family of β-hairpin peptides with systematically introduced chiral inversions, in explicit water, and we investigate the extent to which the backbone structure is able to fold in the presence of heterochiral perturbations. In contrast to the recently investigated case of a helical peptide, we do not find a monotonic change in secondary structure content as a function of the number of L- to D-inversions. The effects of L- to D-inversions are instead found to be highly position-specific. Additionally, in contrast to the helical peptide, some inversions increase the stability of the folded peptide: in such cases, we compute an increase in β-sheet content in the aqueous solution equilibrium ensemble. However, the tertiary structures of the stable (folded) configurations for peptides for which inversions cause an increase in β-sheet content show differences from one another, as well as from the native fold of the nonchirally perturbed β-hairpin. Our results suggest that although some chiral perturbations can increase folding stability, chirally perturbed proteins may still underperform functionally, given the relationship between structure and function.
我们在显式水中计算了一系列具有系统引入的手性反转的β-发夹肽，并研究了在存在异手性扰动的情况下，骨架结构能够在多大程度上折叠。与最近研究的螺旋肽情况不同，我们没有发现二级结构含量随 L 到 D 反转数的单调变化。相反，L 到 D 反转的影响被发现具有高度的位置特异性。此外，与螺旋肽不同，一些反转增加了折叠肽的稳定性：在这种情况下，我们计算了在水溶液平衡系综中β-折叠含量的增加。然而，对于导致β-折叠含量增加的反转肽的稳定（折叠）构象的三级结构彼此不同，也与非手性扰动的β-发夹的天然折叠不同。我们的结果表明，尽管一些手性扰动可以增加折叠稳定性，但考虑到手性与功能之间的关系，手性扰动的蛋白质在功能上可能仍然表现不佳。
