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Another major problem with the PDB is that it does not seem to believe in the existence of different tautomers or protonation states.For example the ATP analogue AMPPNP can have the nitrogen between the beta and gamma phosphates protonated (-P-NH-P) or unprotonated (P-N=P), and there are well documented examples of both tautomers in the PDB (NH being a hydrogen bond donor and N a hydrogen bond acceptor).If you look in the CSD you can see that the protonation state of the nitrogen changes the geometry of the P-N-P bond.However, as I understand it, the PDB considers all tautomeric (and protonated) forms of AMPPNP the same. When I tried to deposit a specific AMPPNP tautomer in 2013, they would not accept it. The PDB also seems to believe, as I understand it, that the overall charge on AMPPNP is zero and that the phosphates do not carry negative charge.Ben BaxSenior Scientific InvestigatorBioMolecular Sciences UKRD Platform Technology & ScienceGSKMedicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UKMobile +44 (0) 7912 600604Tel +44 (0) 1438 55 1156
-----Original Message-----
From: CCP4 bulletin board [mailto:[log in to unmask]] On Behalf Of Martyn Symmons
Sent: 22 June 2015 23:39
To: [log in to unmask]Subject: Re: [ccp4bb] [Fwd: Re: [ccp4bb] FW: New ligand 3-letter code (help-7071)]Well the problem is there is a lot more to a ligand than PDB coordinates - little things like bond orders... In addition people can publish ligands with atoms for which they have no density - so zero-occupancy is allowed too. So who should get priority - the group who publishes a ligand first, or the ones who actually have density for all the atoms?These sorts of complications mean we all benefit from peer-review of the structure - that is why we put things on hold. And authors should have a chance to change their ligand definition based on reviewers'comments - just as they are allowed to improve the PDB coordinates. So it is a worry for them that the PDB might 'publish' the ligand aspect of their work before they have completed the peer-review process.Maybe you don't believe is peer-review - in reply to which I'd paraphrase what people say about democracy - it's pretty bad but better than the alternatives.But to return to the point I made: what really is the problem with maintaining and modifying _separate_ definitions with authors'_separate_ deposited coordinates (and bond orders) while structures are on hold and being reviewed? Journals manage to keep all those submitted papers separate in their databases.cheersM.On Mon, Jun 22, 2015 at 3:12 AM, Edward A. Berry <[log in to unmask]> wrote:>> I can't imagine a journal doing that can you? When I work on my>> supplementary material in a paper I don't expect that the journal>> will take a bit out and publish it separately to support the work of>> my competitors. Not out of spite that I was beaten - but because I>> don't want to take the responsibility for checking their science for them!>>> I don't see the problem here. What about the dozens of authors who> will benefit from using your ligand in their structure _after_ your> structure comes out? You don't take responsibility for checking their> science. Every author gets a copy of his final structure to check> before it is released and each is responsible for his own.> The only difference here is whether the competitor got to use it> first, (which might sting a bit) or only after you had already made it> your own with the first structure.>> I guess the ligand database is the responsibility of the pdb, but they> depend on first depositors to help set up each ligand, so it is not> surprising if the type model has coordinates from the first> depositor's structure (although it would be convenient if they were> all moved to c.o.m. at 0,0,0). When another group publishes a> structure with the ligand, they will not be publishing the first> depositor's coordinates because the ligand will be moved to its> position in their structure and refined against their data, probably> with somewhat different restraints.>> If the ligand is a top secret novel drug lead that your company is> developing I guess it would come as a shock to find someone else has> already deposited it, and it might be good to hasten not the> publication but protecting of the compound with a patent!>> Although Miriam says a new 3-letter code is generated when no match is> found, I believe the depositor's code will be used if it is available,> at least one of mine was last year, so there is some use for Nigel's> utility if you want to stamp your new compound with a rememberable name.>> eab>>> On 06/21/2015 06:33 PM, Martyn Symmons wrote:>>>> Miri raises important points about issues in the PDB Chemical>> Component Dictionary - I think part of the problem is that this is>> published completely separately from the actual PDB - so for example>> I don't think we have an archive of the CCD for comparison alongside>> the PDB snapshots? This makes it difficult to follow the convoluted>> track of particular ligands through the PDB's many,many changes to>> small molecule definitions.>>>> But following discussion with other contributors offline I want to>> make it clear what is my understanding of the ZA3 (2Y2I /2Y59) case:>>>> I am clear there was no unethical behaviour by either group in the>> course of their work on these structures and the publication of them.>>>> The problem I am highlighting is that the PDB don't understand>> publishing ethics - what happened in ZA3 was that they published a>> little bit of one group's work to support the work of someone who was>> scooping them!>>>> I can't imagine a journal doing that can you? When I work on my>> supplementary material in a paper I don't expect that the journal>> will take a bit out and publish it separately to support the work of>> my competitors. Not out of spite that I was beaten - but because I>> don't want to take the responsibility for checking their science for them!>>>> All the best>> Martyn>>>> Cambridge>>>> On Sun, Jun 21, 2015 at 7:01 PM, Miri Hirshberg>> <[log in to unmask]> wrote:>>>>>> Sun., June 21st 2015>>>>>> Good evening,>>>>>> adding several general points to the thread.>>>>>> (1) Fundamentally PDB unlike other chemical databases insists that>>> all equal structures should have the same 3-letter code and the same>>> atom names - obviously for amino acids and say ATP.>>>>>> (1.1) Needless to say there are endless examples in the PDB of two>>> ligands differ by let say one hydroxyl group, where equivalent atoms>>> in the two ligands having totally different names.>>>>>> (2) When a structure is deposited with a ligand, the ligand is first>>> compared against PDB chem_comp database (CCD) and against the>>> on-hold chem_comp (CCD) (naturally the latter is not publicly>>> available), and only if no-match can be found a new three-letter>>> code is generated and assigned.>>>>>> If not, then this is a mistake in annotation and should not happen.>>>>>> (3) Exception to the above take several different flavours. This>>> include:>>>>>> (3.1) When the same ligand is described in PDB as a 3-letters-code>>> and as well as a combination of two different 3-letters-code ligands.>>> An example out of many is phosphoserine. The 3-letter-code in PDB>>> CCD is SEP which is used in 704 PDB entries (RCSB counting>>> 21-June-2015). But in the PDB entry 3uw2 the phosphoserine 109A is>>> described as a combination of SER and the inorganic phosphate PO4 !!!>>> (a side point: note the inorganic PO4 became organic upon this>>> linkage - a PDB chemical conundrum!!).>>>>>> (3.2) CCDC does not make any attempt to standardise atom names nor>>> to match same structures to have equal atom names - original author>>> atom names are kept so that amino acids may have bizarre atom names>>> and where required symmetry atom names are generated - this is rare>>> in the PDB but not unknown, and the PDB is poor at completing>>> atom/ligand names where symmetry is required and in fact often is>>> not completed in any chemical reasonable sense as this would require changes in occupancy.>>>>>> The simplest case is in racemic PDB entries where the symmetry>>> generated structure for say L-ALA should be the D-version DAL, but>>> PDB as is, has not coped with it, as it would require two sets of>>> coordinates each at say 1/2 occupancy (usually).>>>>>> One of several examples in the PDB archive is pdb entry 3e7r. The>>> Xray structure of Racemic Plectasin. The entry consists of one>>> protein chain, in SPG P-1.>>>>>> In the manuscript>>>>>> Figure 3a, for example shows Crystal packing.>>> (a) Centrosymmetric P-1 unit cell. The L-plectasin molecule is shown>>> in blue and the D-plectasin molecule is in gold.>>>>>> But if you use the PDB entry, and the symmetry operator of P-1 to>>> generate the two symmetry related mates in the unit cell you will>>> get a chain with L- naming residues>>> GLY-PHE-GLY-CYS-ASN-GLY-PRO-........ etc representing D- amino>>> acids.>>> (GLY is a special case).>>>>>> (3.3) There is also the problem in assigning a 3-letter code where>>> the submission has obviously assigned the wrong chirality. One>>> example is a where the sugar must be NAG but is assigned NGA in a>>> glycopeptide where NGA is impossible - the PDB should have assigned>>> NAG with a CAVEAT that the chirality is incorrect. Note,>>> re-refinement by other software will require a bond-breakage.>>> NGA is used in 90 entries (RCSB counting 21-June-2015)>>>>>> regards Miri>>>>>>>>>>>>>>>>> From: Yong Wang <[log in to unmask]>>>>>> Reply-to: Yong Wang <[log in to unmask]>>>>>> To: [log in to unmask]>>>>> Subject: Re: [ccp4bb] FW: New ligand 3-letter code (help-7071)>>>>> Date: Sat, 20 Jun 2015 18:36:34 +0000>>>>>>>>>> Sharing a ligand name should only be limited to having the same>>>>> compound, i.e. same 2D structure or connectivity. Each deposition>>>>> should have its own 3D coordinates. If a different publication>>>>> gets your ligand 3D coordinates ("2Y59 actually embodies the>>>>> atomic coordinates from the 2Y2I"), that looks to me an oversight>>>>> by PDB. It is hard to believe that PDB intended to use the 3D>>>>> coordinates from one entry for the other, ligand or not. In fact,>>>>> the restraints as described by the ligand dictionary should also be kept separate as that reflects how the authors refine their ligand.>>>>>>>>>> Yong>>>>>>>>>> -----Original Message----->>>>> From: CCP4 bulletin board [mailto:[log in to unmask]] On Behalf>>>>> Of Martyn Symmons>>>>> Sent: Friday, June 19, 2015 8:39 PM>>>>> To: [log in to unmask]>>>>> Subject: Re: [ccp4bb] FW: New ligand 3-letter code (help-7071)>>>>>>>>>> By oversimplifying the situation here the PDB does not answer my>>>>> related point about competing crystallographers:>>>>> My scenario:>>>>>>>>>> Group A deposits structure with new drug - gets their three-letter>>>>> code for example ZA3 they then get to check the coordinates and>>>>> chemical definition of this ligand.>>>>>>>>>> But suppose a little after that a competing group B deposits their>>>>> structure with the same drug which they think is novel - but no...>>>>> they get assigned the now described ZA3 which has been checked by>>>>> the other group.>>>>>>>>>> Then it is a race to see who gets to publish and release first.>>>>> And if it is the second group B who wins then they are publishing>>>>> the work of their A competitors - who have done the depositing and>>>>> checking of the ligand description.>>>>>>>>>> Sounds unlikely? Well, it actually happened in 2011 for my exact>>>>> example ZA3 - present in 2Y2I and in 2Y59 from competing groups.>>>>>>>>>> From the dates in the mmcif it was 2Y2I depositors who set up>>>>> and had a chance to review the description of ZA3 ligand. Only to>>>>> see it released a week before their crystal structure, when their>>>>> ZA3 appeared to accompany competing 2Y59! It is amazing that the>>>>> PDB did not spot this and arrange a suitable workaround.>>>>>>>>>> Just to check:>>>>> mmcif for ZA3 shows it was created for 2Y2I:>>>>> ...>>>>> _chem_comp.pdbx_model_coordinates_db_code 2Y2I>>>>> ...>>>>> But it was modified for release:>>>>> ...>>>>> _chem_comp.pdbx_modified_date 2011-07-22>>>>> ...>>>>> corresponding to the early 2011-07-27 release date of the>>>>> competing>>>>> structure: 2Y59 even though this PDB was _deposited_ second.>>>>>>>>>> The ZA3 ligand definition released with 2Y59 actually embodies the>>>>> atomic coordinates from the 2Y2I structure:>>>>>>>>>> <mmcif>>>>>> ZA3 O6 O6 O 0 1 N N N 8.279 7.165 40.963 0.311 -1.061 -0.920>>>>> O6 ZA3 1>>>>> ZA3 C5 C5 C 0 1 N N N 9.132 8.047 40.908 0.147 -0.205 -0.073>>>>> C5 ZA3 2 ...>>>>> <PDB 2Y2I>>>>>> HETATM 3598 O6 ZA3 A1000 8.279 7.165 40.963 1.00 41.25>>>>> O>>>>> HETATM 3599 C5 ZA3 A1000 9.132 8.047 40.908 1.00 63.20>>>>> C ...>>>>>>>>>> Surely a better approach would be to allow both groups a chance to>>>>> work through and sign off on independent ligand descriptions?>>>>>>>>>> Then whoever releases first would release both a novel structure>>>>> and the ligand definition _they_ deposited and checked. Their>>>>> priority can then be asserted and the other group contacted to ask>>>>> if they agree to accept this definition. This also has the>>>>> advantage of better confidentiality pre-publication.>>>>>>>>>> Another problem from any cross-linking of definitions is that say>>>>> group A are motivated by reviewers' reports to change the>>>>> definition of ZA3 pre-release. Well now the change impinges on the>>>>> chemical meaning of other group B's deposited structure. For example ZA3 mmcif has a statement:>>>>>>>>>> ZA3 "Modify aromatic_flag" 2011-06-04 RCSB>>>>>>>>>> so this change was pre-release - but we cannot be sure what>>>>> motivated this - whether it was signed off by the 2Y2I authors or>>>>> the 2Y59 authors (or both?)....>>>>>>>>>> With the accelerating pace of drug discovery for sure this sort of>>>>> uncertainty is going to happen again.Unless the PDB have changed>>>>> their practice for ligand deposition?>>>>>>>>>> All the best>>>>> Martyn>>>>>>>>>> Cambridge.>>>>>>>>>> On Fri, Jun 19, 2015 at 1:49 PM, Sheriff, Steven>>>>> <[log in to unmask]> wrote:>>>>>>>>>>>> All:>>>>>>>>>>>>>>>>>>>>>>>> Since the original query was cross-posted on both the COOT>>>>>> mailing list and the CCP4BB Rachel Green gave me permission to>>>>>> forward this to both. She provides links about the mechanism of>>>>>> assignment of 3-letter codes. In the third link below, my>>>>>> original suggestion to the COOT mailing list that one could just>>>>>> use UNK is incorrect as that is reserved for unknown amino acids.>>>>>> According to this document, I should have suggested UNL for an>>>>>> unknown ligand.>>>>>>>>>>>>>>>>>>>>>>>> Steven>>>>>>>>>>>>>>>>>>>>>>>> From: Rachel Kramer Green [mailto:[log in to unmask]]>>>>>> Sent: Tuesday, June 16, 2015 10:21 AM>>>>>> To: Sheriff, Steven>>>>>> Cc: info>>>>>> Subject: Re: New ligand 3-letter code (help-7071)>>>>>>>>>>>>>>>>>>>>>>>> Dear Steven,>>>>>>>>>>>> During annotation of ligands, all chemical components present in>>>>>> the structure are compared against the definitions in the>>>>>> Chemical Component Dictionary (http://www.wwpdb.org/data/ccd). If>>>>>> the ligand is not in the dictionary, a three letter code is>>>>>> assigned. See>>>>>> http://www.wwpdb.org/documentation/policy#toc_assignment. In the>>>>>> future, a group of three-letter codes may be set aside to be used during refinement to flag new ligands.>>>>>>>>>>>> Clarification about the ligand ids assignment and in particular>>>>>> the usage of UNX/UNL/UNK residues can be found at>>>>>>>>>>>> Best wishes,>>>>>> Rachel>>>>>>>>>>>>>>>>>>>>>>>> ________________________________>>>>>>>>>>>> Rachel Kramer Green, Ph.D.>>>>>>>>>>>> RCSB PDB>>>>>>>>>>>> [log in to unmask]>>>>>>>>>>>>>>>>>>>>>>>> New! Deposit X-ray data with the wwPDB at:>>>>>>>>>>>> http://deposit.wwpdb.org/deposition (NMR and 3DEM coming soon).>>>>>>>>>>>> ___________________________________________________________>>>>>>>>>>>> Twitter: https://twitter.com/#!/buildmodels>>>>>>>>>>>> Facebook: http://www.facebook.com/RCSBPDB>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>> On 6/5/2015 7:50 AM, Sheriff, Steven wrote:>>>>>>>>>>>> All:>>>>>>>>>>>>>>>>>>>>>>>> Why the concern for unassigned three-letter codes? The wwPDB>>>>>> isn’t going to let you assign a three-letter code, it will choose>>>>>> its own code.>>>>>>>>>>>>>>>>>>>>>>>> At BMS (a pharmaceutical company), we do many hundreds of>>>>>> structures a year with ligands and we assign the same, already>>>>>> assigned, three-letter code for all of our ligands (unless we>>>>>> have two or more different ligands in a single structure, in>>>>>> which case we use two or more different already assigned>>>>>> three-letter codes). COOT can mostly handle this.>>>>>>>>>>>>>>>>>>>>>>>> However, I believe that if you want an unassigned code, the wwPDB>>>>>> has set aside UNK[nown] for this purpose.>>>>>>>>>>>>>>>>>>>>>>>> Steven>>>>>>>>>>>>>>>>>>>>>>>> From: Mailing list for users of COOT Crystallographic Software>>>>>> [mailto:[log in to unmask]] On Behalf Of Eleanor Dodson>>>>>> Sent: Friday, June 05, 2015 6:28 AM>>>>>> To: [log in to unmask]>>>>>> Subject: Re: New ligand 3-letter code>>>>>>>>>>>>>>>>>>>>>>>> I use your method - trial & error..>>>>>>>>>>>> It would be nice if at least there was a list somewhere of>>>>>> unassigned codes!>>>>>>>>>>>>>>>>>>>>>>>> On 5 June 2015 at 09:16, Lau Sze Yi (SIgN)>>>>>> <[log in to unmask]> wrote:>>>>>>>>>>>> Hi,>>>>>>>>>>>>>>>>>>>>>>>> What is the proper way of generating 3-letter code for a new ligand?>>>>>> As of now, I insert my ligand in Coot using smiles string and for>>>>>> the 3-letter code I picked a non-existent code by trial and error>>>>>> (not very efficient). A cif file with corresponding name which I>>>>>> generated using Phenix was imported into Coot.>>>>>>>>>>>>>>>>>>>>>>>> I am sure there is a proper way of doing this. Appreciate your>>>>>> feedback.>>>>>>>>>>>>>>>>>>>>>>>> Regards,>>>>>>>>>>>> Sze Yi>>>>>>>>>>>>>>>>>>>>>>>> ________________________________>>>>>>>>>>>> This message (including any attachments) may contain>>>>>> confidential, proprietary, privileged and/or private information.>>>>>> The information is intended to be for the use of the individual>>>>>> or entity designated above. If you are not the intended recipient>>>>>> of this message, please notify the sender immediately, and delete>>>>>> the message and any attachments. Any disclosure, reproduction,>>>>>> distribution or other use of this message or any attachments by>>>>>> an individual or entity other than the intended recipient is prohibited.>>>>>>>>>>>>>>>>>>>>>>>> ________________________________>>>>>> This message (including any attachments) may contain>>>>>> confidential, proprietary, privileged and/or private information.>>>>>> The information is intended to be for the use of the individual>>>>>> or entity designated above. If you are not the intended recipient>>>>>> of this message, please notify the sender immediately, and delete>>>>>> the message and any attachments. Any disclosure, reproduction,>>>>>> distribution or other use of this message or any attachments by>>>>>> an individual or entity other than the intended recipient is prohibited.>>>>>
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