These papers may be relevant:
- http://pubs.acs.org/doi/full/10.1021/ci2004658
- https://jcheminf.springeropen.com/articles/10.1186/1758-2946-3-4
On Wed, Jun 29, 2016 at 1:29 AM, Sereina <[email protected]> wrote:
> Hi Tim,
>
> I had a look at the 1DWD example and I detail in the following the
> analysis I did as it may be useful to other users.
>
> The conformer generation function has the option to print the experimental
> torsion preferences that were used in the generation:
> printExpTorsionAngles=True
>
> For 1DWD, it gives the following output:
>
> > ref = Chem.MolFromSmiles('NC(=[NH2+])c1ccc(C[C@
> @H](NC(=O)CNS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCCCC2)cc1’)
> > mol1 =
> Chem.MolFromPDBFile(RDConfig.RDBaseDir+'/rdkit/Chem/test_data/1DWD_ligand.pdb')
> > mol1 = AllChem.AssignBondOrdersFromTemplate(ref, mol1)
> > mol1 = Chem.AddHs(mol1)
> > numConfs = 100
> > cids = AllChem.EmbedMultipleConfs(mol1, numConfs=numConfs,
> useExpTorsionAnglePrefs=True, useBasicKnowledge=True,
> printExpTorsionAngles=True)
> O=[S:1](=O)[NX3H1:2]!@;-[CX4H2:3][!#1:4]: 0 13 14 15, (17.9, -13.3, 9.2,
> 4.7, -2.3, -0.9)
> O=[C:1][NX3H1:2]!@;-[CX4H1:3][H:4]: 15 17 18 48, (5, 0, 0, 0, 0, 0)
> [O:1]=[CX3:2]!@;-[NX3H0:3][!#1:4]: 20 19 31 32, (0, 8, 0, 0, 0, 0)
> [O:1]=[CX3:2]!@;-[NX3H1:3][!#1:4]: 16 15 17 18, (100, 0, 0, 0, 0, 0)
> [c:1][S:2](=O)(=O)!@;-[NX3H1:3][C:4]: 4 0 13 14, (0, 16, 5, 7, 0, 0)
> [aH1:1][c:2]([aH1])!@;-[SX4:3][!#1:4]: 3 4 0 13, (0, 1.5, 0, 0, 0, 0)
> N[C:2](=[O:1])!@;-[CH2:3][N:4]: 16 15 14 13, (0, 10, 0, 0, 0, 0)
> [!#1:1][CX4:2]!@;-[CX4:3][!#1:4]: 17 18 21 22, (0, 0, 7, 0, 0, 0)
> [NH1:1][CX4:2]!@;-[CX3:3]=[O:4]: 17 18 19 20, (0, 2.1, -0.1, -1, -0.4,
> -0.1)
> [cH1:1][c:2]([cH1])!@;-[CX4H2:3][CX4:4]: 23 22 21 18, (0, 3.6, 0, 0, 0, 0)
> [a:1][c:2]!@;-[C:3](=[N:4]): 25 27 28 30, (0, 5, 0, 0, 0, 0)
> [*:1][X3,X2:2]=[X3,X2:3][*:4]: 27 28 30 57, (0, 100, 0, 0, 0, 0)
>
> The output is structured as follows: First comes the SMARTS pattern, then
> the indices of the four atoms involved and finally the six force constants
> K_1, K_2, K_3, K_4, K_5, K_6 for the torsion potential (see Eq. (2) in
> JCIM, 55, 2562, 2015).
> The position of the non-zero force constant tells you the multiplicity i
> of the cosine. E.g. for the torsion between atoms 18 and 21 the third force
> constant is 7.0 and all others are zero, thus the torsion potential for
> this bond has a multiplicity i = 3 (i.e. three maxima). The information
> about the phase shift is not exposed, but we can change that if people find
> it useful.
> Currently to get the full information about the torsion potential, you
> need to search for the SMARTS pattern in
> Code/GraphMol/ForceFieldHelpers/CrystalFF/TorsionPreferences.cpp
> There you find the line: "[!#1:1][CX4:2]!@;-[CX4:3][!#1:4] 1 0.0 1 0.0 1
> 7.0 1 0.0 1 0.0 1 0.0\n"
> Here we have twelve parameters, always two for a given multiplicity: first
> the phase shift (can be 1 or -1) and second the force constant.
> For this particular torsion pattern we have a multiplicity of 3, a phase
> shift of cos(d) = 1 and a force constant K_3 = 7.0, which corresponds to
> three peaks at 60°, 180° and 300° in the range [0°, 360°] (or -60°, 60° and
> 180° in the range [-180°, 180°]).
>
> The two bonds connecting the benzamidine ring to the rest of the molecule
> are between atoms 22/21 and 21/18.
> I calculated the signed dihedral angle for these two bonds, here is the
> code for the second one:
>
> > angles = []
> > for cid in cids:
> > conf = mol1.GetConformer(id=cid)
> > # torsion of atoms 17 18 21 22
> > p1 = conf.GetAtomPosition(17)
> > p2 = conf.GetAtomPosition(18)
> > p3 = conf.GetAtomPosition(21)
> > p4 = conf.GetAtomPosition(22)
> > a = Geometry.ComputeSignedDihedralAngle(p1, p2, p3, p4)/math.pi *
> 180.0
> > angles.append(a)
>
> For 100 confs, this gives the following distribution:
> So, the torsion potential is sampled as it is supposed to do.
>
>
> For the other bond between atmos 22/21, we have the following line in
> TorsionPreferences.cpp:
> "[cH1:1][c:2]([cH1])!@;-[CX4H2:3][CX4:4] 1 0.0 1 3.6 1 0.0 1 0.0 1 0.0 1
> 0.0\n”
> This means, we have a multiplicity of 2, a phase shift cos(d) = 1 and a
> force constant of 3.6, which corresponds to two peaks at -120° and 120° in
> the range [-180°, 180°].
> The histogram looks like:
> Again, the potential is largely sampled as it’s supposed to be.
>
> Now, let’s have a look at the two bonds connecting atom 18 to the other
> two branches.
> For the bond between atoms 18/17, we should have a single peak at 0°,
> which we get most of the time
>
> The bond between atoms 18/19 has a multi-term potential, which is a bit
> more difficult to interpret from the numbers alone.
> "[NH1:1][CX4:2]!@;-[CX3:3]=[O:4] 1 0.0 -1 2.1 -1 -0.1 -1 -1.0 1 -0.4 1
> -0.1\n"
> It has three peaks at -150°, 0° and 150° in the range [-180°, 180°]. The
> peak at 0° is broad.
> The histogram looks like:
> For the 100 conformers, the peaks at -150° and 150° are not sampled. I
> therefore generated 1000 conformers, but the sampling does not really
> improve:
>
> The algorithm of ETKDG takes a randomly generated conformer from standard
> distance geometry and minimizes it with the ET and K terms. For each bond
> with an exp. torsion term, the torsional angle will be minimized to the
> closest minima. In other words, ETKDG relies on distance geometry for the
> sampling. Nevertheless, I will have a look at this particular pattern in
> the next version of ETKDG to see if we can improve it.
>
> Best,
> Sereina
>
>
>
> On 22 Jun 2016, at 10:41, Tim Dudgeon <[email protected]> wrote:
>
> This topic (https://sourceforge.net/p/rdkit/mailman/message/35173301/)
> discussed using conformer generation as input into Open3DAlign.
>
> One thing I noticed is that the conformer generation (using the
> useExpTorsionAnglePrefs=True and
> useBasicKnowledge=True options) does not generate conformers that align
> well for this example. The input is based on the 1DWD_ligand.pdb
> structure in the RDKit distro. What I find is the the rotation of the
>
> benzamidine ring is never in the right place for alignment (the other
> two ring systems align well). This is when generating up to 10,000
> conformers.
>
> Does this suggest that the conformer generation does not sample
> conformational space very effectively? Are there options for improving
> this?
>
> Thanks
>
> Tim
>
>
>
>
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