Faculty of Production Engineering, Bremen Center for Computational Materials Science, Center for Environmental Research and Sustainable Technology (UFT), and MAPEX Center for Materials and Processes , Hybrid Materials Interfaces Group, University of Bremen , Am Fallturm 1 , Bremen 28359 , Germany.
Biomolecular and Materials Interface Research Group, Interdisciplinary Biomedical Research Centre, School of Science and Technology , Nottingham Trent University , Clifton Lane , Nottingham NG11 8NS , United Kingdom.
J Phys Chem B. 2019 Aug 8;123(31):6694-6704. doi: 10.1021/acs.jpcb.9b03932. Epub 2019 Jul 25.
Although successful in the structural determination of ordered biomolecules, the spectroscopic investigation of oligopeptides in solution is hindered by their complex and rapidly changing conformational ensemble. The measured circular dichroism (CD) spectrum of an oligopeptide is an ensemble average over all microstates, severely limiting its interpretation, in contrast to ordered biomolecules. Spectral deconvolution methods to estimate the secondary structure contributions in the ensemble are still mostly based on databases of larger ordered proteins. Here, we establish how the interpretation of CD spectra of oligopeptides can be enhanced by the ability to compute the same observable from a set of atomic coordinates. Focusing on two representative oligopeptides featuring a known propensity toward an α-helical and β-hairpin motif, respectively, we compare and cross-validate the structural information coming from deconvolution of the experimental CD spectra, sequence-based de novo structure prediction, and molecular dynamics simulations based on enhanced sampling methods. We find that small conformational variations can give rise to significant changes in the CD signals. While for the simpler conformational landscape of the α-helical peptide de novo structure prediction can already give reasonable agreement with the experiment, an extended ensemble of conformers needs to be considered for the β-hairpin sequence.
尽管在有序生物分子的结构确定方面取得了成功，但由于寡肽在溶液中复杂且快速变化的构象集合，其光谱研究受到阻碍。寡肽的测量圆二色性 (CD) 光谱是所有微态的集合平均值，严重限制了其解释，与有序生物分子形成对比。用于估计集合中二级结构贡献的光谱解卷积方法仍然主要基于较大有序蛋白质的数据库。在这里，我们展示了通过从一组原子坐标计算相同可观测值的能力，如何增强对寡肽 CD 光谱的解释。我们专注于两个具有已知倾向于形成 α-螺旋和 β-发夹结构的代表性寡肽，分别比较和交叉验证来自实验 CD 光谱解卷积、基于序列的从头预测结构和基于增强采样方法的分子动力学模拟的结构信息。我们发现，小的构象变化会导致 CD 信号发生显著变化。对于 α-螺旋肽较简单的构象景观，从头预测结构已经可以与实验很好地吻合，但对于 β-发夹序列，需要考虑扩展的构象集合。
