From: Shveta Bisht
Date: 9 January 2012 06:13
Dear all
I have generated a refmac cif file for a molecule using PRODRG. I used
JME editor to draw the molecule and ran PRODRG online with the
options: Chirality-Yes, Charges-Reduced and EM-Yes. Please check the
attachments for the molecule drawing and the expected bond lengths as
listed in the PRODRG generated cif file. There are some unusual
values. I have listed them below along with the likely explanations
(just guesses).
DRG CAR CAK single 1.390 0.025
DRG CAQ CAB single 1.390 0.025
DRG CAT CAI single 1.390 0.020
All three are C-C single bonds where one of the carbons belong to
aromatic ring. This might lead to a short bond, although 1.39 seems to
be too short for this.
DRG CAI NAL double 1.340 0.022
DRG CAP NAL single 1.340 0.022
Here N and both the carbons are sp2 hybridization, so there can be
delocalization of electrons. Thus both bonds (single and double) are
of similar length.
DRG CAP CAA double 1.530 0.025
As mentioned above, if pi (unhybridized) electrons of CAP are involved
in CAP NAL bonding, then CAP CAA double bond essentially becomes a
single bond with 1.53 bond length.
I need advise on the way I have run prodrg and the explanations for the results.
Is it common to observe such values? Or it is due to the alternating single and
double bonds in this structure.
--
Shveta Bisht
Ph.D. Student,
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From: krish
Dear Shveta,
I have seen similar trends with PRODRG. I recommend you to use other molecular modeling programs like Hyperchem or Maestro to get more consistent geometric parameters for small molecules. Once you know the bondlengths and bond angles from aforesaid molecular modeling programs, you can use sketcher (CCP4) to define them manually. Save it to the monomer library and you are all set to run them in Refmac .
or
You can use Phenix.elbow or phenix.reel to load the coordinates of the small moleucle and optimize with AM1 (semi-empirical), then you should get reasonable geometirc parameters suc as bond length, bond angles and etc.
Hope this helps !
Cheers,
Krishna
Krishna Chinthalapudi, PhD
Hannover Medical School
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From: Paul Emsley
There is little room for manoeuvre when running prodrg.
Prodrg is not the Font of All Ligand Wisdom.
Prodrg makes mistakes.
If you think that the bond lengths are wrong, change them.
You can use CCDC's Mogul to assist in the restraints manipulation. You can test this yourself by generating different but related ligands.
You might like to use the CCP4 version rather than the web version which it seems that you are currently using.
Other restraints-generating software is available.
HTH,
Paul.
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From: Eleanor Dodson
Thank you Shveta for NOTICING!!!
Please - everyone - check your restraints - programs make mistakes - you (or the chemist who made the ligand) - are the experts!!!!
Eleanor----------
From: Ian Tickle
Dear Shveta
I agree completely with your assessment, there are certainly some
"unusual" values, but I think this goes beyond "mistakes". I have run
your structure through our own dictionary auto-generation software
which essentially takes suitable fragments from the CSD and stitches
them together (similar to CCDC-MOGUL but it doesn't use MOGUL and the
pieces are smaller).
Here are the values I get for comparison:
> DRG CAR CAK single 1.390 0.025 1.512(10)
> DRG CAQ CAB single 1.390 0.025 1.498(7)
> DRG CAT CAI single 1.390 0.020 1.449(24)
> DRG CAI NAL double 1.340 0.022 1.273(13)
> DRG CAP NAL single 1.340 0.022 1.350(28)
> DRG CAP CAA double 1.530 0.025 1.329(21)
so essentially backing up what you said.
My suspicion is that it's not generally recognised the central role
played by bond length & angle restraints in MX refinement (after all
if they weren't important then we wouldn't need to use them!), and as
a consequence some people seem to think that their exact values are
unimportant and "anything will do". Their importance soon becomes
obvious (particularly of course at medium-low resolution) if you try
to do unrestrained refinement: then you can easily get deviations 10
times greater than you get with restraints. So personally I believe
in using the most accurate restraints possible and "anything will NOT
do".
My main concern would be that grossly inaccurate values such as these
find their way into the PDB and then people base their restraints on
these structures (though it's not a great idea to use the PDB
co-ordinates as a source of restraints!).
Before you ask, unfortunately our software is not available for
distribution but I can recommend GRADE from Global Phasing which gives
very high quality restraints; there's also of course JLigand from
CCP4, though I haven't used it personally and so cannot attest for the
quality.
Cheers
-- Ian
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From: Soisson, Stephen M
I will second Ian's recommendation for GRADE from the Global Phasing group. GRADE overcomes nearly all of the shortcomings we have encountered with other approaches for ligand dictionary generation.
Best-
Steve
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From: Tom Peat
To elaborate further on software packages available that do a reasonable job of fitting small molecules and outputting reasonable dictionaries, one could consider Afitt from OpenEye Scientific Software. They have academic as well as commercial licenses to their software.
Cheers, tom
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From: Colin Groom
I'm sad to think that scientists may not 'bother' to use the CSD system 'just' to check the geometry of small molecule ligands, as they may, of course, be the main focus of the study, or the focus of subsequent researchers who use the structures. Moreover, comparison of small molecule and protein-bound ligand structures can be most revealing.
In answer to your question of access, the vast majority of research universities in the world (with a chemistry department) already have access to the CSD. In fact it is available in 72 counties, to scientists in around 1,500 institutions. The problem you highlight is that it's quite common for scientists not to realise that another department, or their institutions library, already provide access to the CSD system. I'll reply to any off-board emails should folks want to know who their local contact is.
In terms of affordability, the CSD system is maintained by the Cambridge Crystallographic Data Centre, which is a non-profit, charitable organisation. It is available at below cost to academics. Anyone who genuinely cannot afford the modest charge, which is used for the ongoing funding of the CSD, is of course given free access. The CSD and other chemistry databases are also freely available to UK researchers through the excellent (EPSRC funded) Chemical Database Service operated from Daresbury.
You're right that the CCDC:PDB collaboration to develop on-line tools check ligands and generate dictionaries 'is great'- and Gerard might let us know how he's getting on?
Colin
How many academic labs will bother / can afford to buy a CCSD license
just to check the geometry of small molecule ligands, especially when
they need to do so them only once every blue moon?
The ability for the PDB to check a ligand against the CCSD upon
deposition would be great. The ability to generate the restraint
definition for free via the web before deposition is better: that's
why people use PRODRG!
Stephen
> Dear Shveta,
>
> I'd like to follow up Ian Tickle's answer. A survey we carried out recently suggested that up to 70% of ligand structures in the PDB had bond and bond angle errors that could have been removed by better choice of restraints (to be published). Although most of the errors found are small, some were very large (> 10 s.d. from mean).
>
> The Mogul program (
http://www.ccdc.cam.ac.uk/products/csd_system/mogul/) can be used to analyse the geometry of any feature in a 3D ligand model against data in the Cambridge Structural Database and is available to anyone who has access to the Cambridge Structural Database System. The GRADE dictionary generation software from Global Phasing uses Mogul information behind the scenes to generate bond and bond angle restraints. In addition ligand validation and restraint correction using Mogul will become available via COOT before too long. Finally you might like to know we are working with the PDB so that the geometry of ligand models can be validated on submission.
>
> Regards
> John
>
> Dr John W. Liebeschuetz
>
>
>
--
Dr Stephen Graham
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From: Martyn Winn
Thanks Colin! I was also going to mention the Chemical Database Service,
available to UK academics.
Their website is
http://cds.dl.ac.uk/ In fact, the very nice and friendly CDS guys are just across the
corridor from me, so please let me know if you have problems/questions.
Cheers
Martyn
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From: dusan turk
Hi Guys,
I just want to make aware that apart form PRODRG etc there exist also PURY server http://pury.ijs.si/, which offers a possibility to create restraints for heteromolecules. It accepts PDB files, smiles format. Alternatively JME editor can be used to draw your compound.
PURY: a database of geometric restraints of hetero compounds for refinement in complexes with macromolecular structures
Miha Andrejasˇicˇ, Jure Prazˇnikar and Dusˇan Turk
Acta Cryst. (2008). D64, 1093–1109)
Its parameters are extracted from CSD. Its unlimited use is restrained to the CSD license holders, whereas for a small number of downloads its use is not restrained.
dusan
