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.