Incorporating NOE-Derived Distances in Conformer Generation of Cyclic Peptides with Distance Geometry

Nuclear
magnetic resonance (NMR) data from NOESY (nuclear Overhauser
enhancement spectroscopy) and ROESY (rotating frame Overhauser enhancement
spectroscopy) experiments can easily be combined with distance geometry
(DG) based conformer generators by modifying the molecular distance
bounds matrix. In this work, we extend the modern DG based conformer
generator ETKDG, which has been shown to reproduce experimental crystal
structures from small molecules to large macrocycles well, to include
NOE-derived interproton distances. In noeETKDG, the experimentally
derived interproton distances are incorporated into the distance bounds
matrix as loose upper (or lower) bounds to generate large conformer
sets. Various subselection techniques can subsequently be applied
to yield a conformer bundle that best reproduces the NOE data. The
approach is benchmarked using a set of 24 (mostly) cyclic peptides
for which NOE-derived distances as well as reference solution structures
obtained by other software are available. With respect to other packages
currently available, the advantages of noeETKDG are its speed and
that no prior force-field parametrization is required, which is especially
useful for peptides with unnatural amino acids. The resulting conformer
bundles can be further processed with the use of structural refinement
techniques to improve the modeling of the intramolecular nonbonded
interactions. The noeETKDG code is released as a fully open-source
software package available at www.github.com/rinikerlab/customETKDG.

核磁共振（NMR）数据，源自NOESY（核奥弗豪泽增强光谱学）和ROESY（旋转框奥弗豪泽增强光谱学）实验，可通过修改分子距离界限矩阵，与基于距离几何（DG）的构象生成器轻易结合。在本研究中，我们将现代基于距离几何的构象生成器ETKDG的应用范围扩展，该生成器已被证实能够良好地复现从小分子到大型环状化合物的实验晶体结构，并纳入由NOE（核偶极自旋转移）得到的质子间距离。在noeETKDG中，通过实验获得的质子间距离被纳入距离界限矩阵作为宽松的上限（或下限），以生成大量的构象集合。随后，可以应用多种子选择技术，以获得最佳地复现NOE数据的构象包。该方法通过一组24个（大部分为环状）肽段进行基准测试，这些肽段提供了由NOE得到的距离以及其他软件获取的参考解构数据。与其他现有的软件包相比，noeETKDG的优势在于其速度和无需预先进行力场参数化，这对于含有非天然氨基酸的肽段尤其有用。生成的构象包可以进一步通过结构精修技术进行处理，以优化分子内非键相互作用建模。noeETKDG代码作为一个完全开源的软件包发布，可在www.github.com/rinikerlab/customETKDG获取。