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）谱数据，包括NOESY（核Overhauser增强光谱学）和ROESY（旋转框Overhauser增强光谱学）实验数据，可通过调整分子距离界限矩阵，轻松与基于距离几何（DG）的构象生成器相结合。在本研究中，我们扩展了现代基于DG的构象生成器ETKDG，该生成器已被证明能够从小分子到大型环状化合物准确复现实验晶体结构，并纳入了由NOE（核Overhauser效应）得到的质子间距离。在noeETKDG中，实验得到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），以生成大量构象集。随后，可以应用各种子选择技术，以获得最佳复现NOE数据的构象束。该方法通过一套24个（主要是）环状肽的数据集进行基准测试，这些数据集提供了NOE得到的距离以及其他软件获得的参考解构象。与现有其他软件包相比，noeETKDG的优势在于其速度以及无需先前的力场参数化，这对于含有非天然氨基酸的肽特别有用。生成的构象束可以通过结构精炼技术进一步处理，以优化分子内非键合相互作用的建模。noeETKDG代码作为完全开源的软件包发布，可在www.github.com/rinikerlab/customETKDG获取。