[Rdkit-discuss] conformation search and constraints

[Rafal R. <rmr...@gm...>]

Hello,

I want to find: 
A) "global minimum" [*] for given compound(s) and 
B) (for the same compound) minimum with constraint(s) (e.g. frozen
angle)

For problem A) I tried folowing code:

self.MOLEC=Chem.MolFromSmiles(SMILES)
self.MOLEC=Chem.AddHs(self.MOLEC)
allconf=Chem.rdDistGeom.EmbedMultipleConfs(self.MOLEC,
numConfs=HowMany, enforceChirality=True, pruneRmsThresh=limitRMS) for
confId in range(len(allconf)): AllChem.UFFOptimizeMolecule(self.MOLEC,
maxIters=12540, confId=confId) self.ff =
AllChem.UFFGetMoleculeForceField(self.MOLEC) energy_value = str
(self.ff.CalcEnergy()) print (energy_value)


No matter what values are used for the numConfs or pruneRmsThresh after
optimization I end up in conformer(s) with the same energy. The energy
value vary from one run to another. In other words EmbedMultipleConfs()
generate random structure (that make sense to me) but all conformation
are very similar - after optimization all fall into one structure. Is
it bug or feature? :) How effectively generate set of _different_
conformation? I found two solution: a) execute presented above code
multiple times b) set dihedral angle to unnatural value (using
Chem.rdMolTransforms.SetDihedralDeg() function) for selected dihedral
angle and then minimize structure Both works but seems to me that both
are not optimal.


For problem B:

I want to minimize structure with frozen dihedral angle. I set the
angle value using Chem.rdMolTransforms.SetDihedralDeg I could not find
any possibility to freeze angle so I used
rdForceField.ForceField.MMFFAddTorsionConstraint function. with very
high forceConstant (relative=True minDihedralDeg=-5, maxDihedralDeg=5,
forceConstant=9999999.9). The code is as follow:


conformers=Chem.rdDistGeom.EmbedMultipleConfs(self.MOLEC,numConfs=confNum, enforceChirality=enforceChirality,numThreads=numThreads, pruneRmsThresh=RMSThreshold)
for confId in range(len(conformers)):
	ff = AllChem.UFFGetMoleculeForceField(self.MOLEC, confId=confId)
        rdForceField.ForceField.MMFFAddTorsionConstraint( ff, idx0, idx1, idx2, idx3, True, minDihedralDeg=-5, maxDihedralDeg=5, forceConstant=9999999.9)
	Chem.rdMolTransforms.SetDihedralDeg(self.MOLEC.GetConformer(confId), idx0, idx1, idx2, idx3, 0.0 )
	AllChem.UFFOptimizeMolecule(self.MOLEC, maxIters=12540, confId=confId)

but it does not work - i end up in structure with dihedral value far from this which was set. How can I force optimization with defined value (or some range of values)? In other words what I am doing wrong?

Regards,

Rafal




[*] Yes I aware that it is very complex task to find a true global
minima but I only want to find reasonably good/stable conformer, that
why I wrote "global minimum"