Hi Paul, TFD was developed for drug-like molecules with small rings. The torsions of ring bonds are therefore summed up into a single average value for each ring (see Figure 1 in J. Chem. Inf. Model., 52, 1499, 2012). This makes of course not much sense for a macrocycle and likely causes your results.
If you are interested in the macrocycle conformation alone, I would recommend to either use ringRMSD (with or without beta-atoms) or a torsional-angle RMSD (careful with the periodicity). The latter has the advantage that no alignment is needed. Examples for the use of ringRMSD with macrocycles are in the ETKDG version 3 paper (J. Chem. Inf. Model., 60, 2044, 2020) or the recent noeETKDG paper (https://pubs.acs.org/doi/10.1021/acs.jcim.1c01165). Hope this helps. Best, Sereina > On 19 Jan 2022, at 16:37, mix_of_reasons via Rdkit-discuss > <rdkit-discuss@lists.sourceforge.net> wrote: > > > Hi RDKitters, > > I am using the RDKit implementation of TFD to examine conformational > differences between macrocycles and to cluster their conformations. In some > basic testing of a set of conformations of the same macrocycle from the PDB I > find something unexpected: > > #mollist = list of conformations of the same molecule from the PDB > > tfds = [] > rmsds = [] > for m in mollist: > for n in mollist: > tfd = TorsionFingerprints.GetTFDBetweenMolecules(m, n, maxDev='spec', > useWeights=False) > rmsd = GetBestRMS(m,n) > tfds.append(tfd) > rmsds.append(rmsd) > > #Plot the two lists > > <image.png> > > Comfortingly, all cases of RMS = 0 also give TFD = 0. > According to the original paper a TFD of 1 implies maximal torsional > deviation, yet here I see a very low RMSD (0.3-4A, essentially insignificant > for molecules of this size) at TFD = 1. > Also useWeights = True in the code above gives TFDs > 1, which is clearly not > possible in the spirit of the original idea, but probably arises from there > not really being a graph centre in a macrocycle. > > The idea of clustering macrocycles based on some measure of distance in > torsion space is very appealing, but I am concerned by TFD = 1 being > calculated for conformations that have essentially the same geometry. Any > suggestions on how to proceed? > > > Paul. > > > Sent with ProtonMail <https://protonmail.com/> Secure Email. > > _______________________________________________ > Rdkit-discuss mailing list > Rdkit-discuss@lists.sourceforge.net > https://lists.sourceforge.net/lists/listinfo/rdkit-discuss
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