Dear Paul, I find it difficult to predict when a pipirazine nitrogen will be sp2 and when sp3, so I usually search the csd with the exact substituent at hand and supposed that Joel will have done the same. In general, I find that auto generate programs are overly optimistic how far delocalization of binding electrons will extend, and also about the effect of steric hindrance by other substituents at staggered positions. So in general, compounds tend to be in reality less flat than cif generating programs think. It is also important to carefully look at the electron density maps and the fit of the compound. With large substituents like phenyl groups, choosing the wrong conformation should produce significant distortions.
Best, Herman Von: CCP4 bulletin board [mailto:[email protected]] Im Auftrag von Paul Emsley Gesendet: Dienstag, 15. April 2014 10:28 An: [email protected] Betreff: Re: [ccp4bb] AW: appropriate torsion angles Dear Joel and Herman, On 15/04/14 04:39, [email protected]<mailto:[email protected]> wrote: Dear Joel, I always tell our chemists not to include piperazine rings etc. in their compounds because of this conformational mess, but somehow they do not seem to listen. ;-) Unfortunately, do did not tell us how and with software you auto generated your cif file, so I can only give some general remarks: I would try grade from global phasing to generate your cif file. Grade uses Mogul, which consults the CSD to find the appropriate conformational parameters. Is you nitrogen flat, or has it the wrong chirality? If the chirality is wrong, you should change all _chem_comp_chir.volume_sign's from positive/negative to both. However, real-space refinement will usually not get through the energy barrier to change the chirality, so you will have to move the atoms manually. In the "Rotate Translate Zone" mode, you can move individual atoms by pressing <cntrl> and picking the atom with the left mouse button. FWIW, for this sort of thing I usually fix atoms before refinement and ctrl-move fixed atoms during refinement. If one of the R groups is merely a hydrogen, coot's refinement pathology detection should jump the hydrogen to the other side of incorrect chiral centres. You may need to try this in "regularization mode" sometimes. In my experience, without a formal charge prodrg likes to make piperazine nitrogens sp2 if connected to at least one aromatic carbon (as in Joel's case - at least in my reading). This may well be The Right Thing to do, so the whole boat/chair thing is a bit moot. If the nitrogen is flat and you auto generate from a pdb file, you should make sure the nitrogen on the input file has a tetrahedral conformation. You may force the program to make a tetrahedral nitrogen by adding a proton (and positive charge) or remove the phenyl and copy the nitrogen parameters generated to the cif file for the complete molecule, but better would be to use grade. Best, Herman Von: CCP4 bulletin board [mailto:[email protected]] Im Auftrag von Joel Tyndall Gesendet: Dienstag, 15. April 2014 07:03 An: [email protected]<mailto:[email protected]> Betreff: [ccp4bb] appropriate torsion angles Hi folks, We are trying to model multiple instances of a small molecule that contains a piperazine ring. I am looking for the appropriate torsion angles that are needed for a cif file in order for the piperazine ring to be able to adopt either a chair or a boat or any combination between the two (i.e. relaxed torsion restraints but remaining tetrahedral). Have you ever seen convincing density for a boat piperazine in PDB data? (given sp3 hybrization, of course) Any help would be much appreciated before I launch into writing a new cif file from scratch. As a little background, the piperazine contains a phenyl substituent on the nitrogen which is tetrahedral according to the CSD for small molecules. This has meant that the auto generated cif files gave the wrong geometry for the nitrogen in the first place. Many thanks
