[phenixbb] geometry_minimization makes molprobity score worse

James Holton jmholton at lbl.gov
Thu Jul 8 12:49:55 PDT 2021


Thank you Nigel,

Rama-Z "before" (amber energy minimization):
   Rama-Z (Ramachandran plot Z-score):
   Interpretation: bad |Rama-Z| > 3; suspicious 2 < |Rama-Z| < 3; good 
|Rama-Z| < 2.
   Scores for whole/helix/sheet/loop are scaled independently;
   therefore, the values are not related in a simple manner.
     whole: -0.32 (0.86), residues: 62
     helix:  0.09 (1.50), residues: 12
     sheet:  None (None), residues: 0
     loop : -0.27 (0.70), residues: 50

after phenix.geometry_minimization
     whole: -3.20 (0.87), residues: 62
     helix:  None (None), residues: 0
     sheet: -3.03 (1.30), residues: 12
     loop : -2.05 (0.72), residues: 50

repeated with cdl=False
   whole: -3.35 (0.90), residues: 62
   helix:  None (None), residues: 0
   sheet: -4.51 (1.09), residues: 10
   loop : -1.90 (0.75), residues: 52



pdbs and logs are tarballed here:
https://bl831.als.lbl.gov/~jamesh/bugreports/phenixmin_070721.tgz


On 7/8/2021 11:16 AM, Nigel Moriarty wrote:
> James
>
> This is very interesting from a different perspective but I should 
> point out a few things.
>
> 1. The CDL, which is the default, changes the backbone bonds and 
> angles based on phi/psi. Maybe in geometry minimisation this is 
> causing the "whirlygig." Can you check with cdl=False?
>
> 2. In a recent pub
>
>  1. Sobolev OV, Afonine PV, Moriarty NW, Hekkelman ML, Joosten RP,
>     Perrakis A, Adams PD: *A Global Ramachandran Score Identifies
>     Protein Structures with Unlikely Stereochemistry.*
>     /Structure/ 2020, *28*:1249-1258.e2.
>     <http://dx.doi.org/10.1016/j.str.2020.08.005> [PMID: 32857966]
>     [PMCID: PMC7642142]
>
> we argue that percent favoured is not an accurate measure of Rama 
> health. Could also provide these numbers?
>
> Cheers
>
> Nigel
>
> ---
> Nigel W. Moriarty
> Building 33R0349, Molecular Biophysics and Integrated Bioimaging
> Lawrence Berkeley National Laboratory
> Berkeley, CA 94720-8235
> Phone : 510-486-5709     Email : NWMoriarty at LBL.gov
> Fax   : 510-486-5909      Web  : CCI.LBL.gov <http://CCI.LBL.gov>
> ORCID : orcid.org/0000-0001-8857-9464 
> <https://orcid.org/0000-0001-8857-9464>
>
>
> On Thu, Jul 8, 2021 at 10:28 AM James Holton <jmholton at lbl.gov 
> <mailto:jmholton at lbl.gov>> wrote:
>
>     Thank you Pavel for your prompt response!
>
>     I agree with everything you wrote below, and that is a good point
>     about 2nd derivatives.
>
>     However, what I'm seeing is the opposite of what you might
>     predict. See below.
>
>     On 7/7/2021 11:27 PM, Pavel Afonine wrote:
>>     Hi James,
>>
>>     thanks for email and sharing your observations!
>>
>>>     Greetings all, and I hope this little observation helps improve
>>>     things somehow.
>>>
>>>     I did not expect this result, but there it is. My MolProbity
>>>     score goes from 0.7 to 1.9 after a run of
>>>     phenix.geometry_minimization
>>>
>>>     I started with an AMBER-minimized model (based on 1aho), and
>>>     that got me my best MolProbity score so far (0.7). But, even
>>>     with hydrogens and waters removed the geometry_minimization run
>>>     increases the clashscore from 0 to 3.1 and Ramachandran favored
>>>     drops from 98% to 88% with one residue reaching the outlier level.
>>
>>     It is not a secret that 'standard geometry restraints' used in
>>     Phenix and alike (read Refmac, etc) are very simplistic. They are
>>     not aware of main chain preferential conformations (Ramachandran
>>     plot), favorable side chain rotamer conformations. They don't
>>     even have any electrostatic/attraction terms -- only anti-bumping
>>     repulsion! Standard geometry restraints won't like any NCI
>>     (non-covalent interaction) and likely will make interacting atoms
>>     break apart rather than stay close together interacting.
>
>     Yes, there's the rub: I'm not seeing "interacting atoms break
>     apart", but rather they are being smashed together. Torsion angles
>     are also being twisted out of allowed regions of the Ramachandran
>     plot.
>
>     All this with the x-ray term turned off!
>
>>     With this in mind any high quality (high-resolution) atomic model
>>     or the one optimized using sufficiently high-level QM is going to
>>     have a more realistic geometry than the result of geometry
>>     regularization against very simplistic restraints target. An
>>     example:
>>
>>     https://journals.iucr.org/d/issues/2020/12/00/lp5048/lp5048.pdf
>>     <https://journals.iucr.org/d/issues/2020/12/00/lp5048/lp5048.pdf>
>>
>>     and previous papers on the topic.
>
>     I agree, but what doesn't make sense to me is how the "simplistic
>     restraints" of phenix.geometry_minimization would be so
>     inconsistent with the "simplistic restraints" in phenix.molprobity ?
>
>     What I am doing here is starting with an energy-minimized model of
>     a 1.0 A structure (1aho). It's not a fancy QM, just the ff14SB
>     potential in AMBER.  I get my best molprobity scores this way, but
>     I need an x-ray refinement program like phenix.refine to compare
>     these models with reality.  It troubles me that the "geometry" in
>     the x-ray refinement program all by itself messes up my molprobity
>     score.
>
>>
>>>     Just for comparison, with refmac5 in "refi type ideal" mode I
>>>     see the MolProbity rise to 1.13, but Clashscore remains zero,
>>>     some Ramas go from favored to allowed, but none rise to the
>>>     level of outliers.
>>
>>     I believe this is because of the nature of minimizer used. Refmac
>>     uses 2nd derivative based one, which in a nutshell means it can
>>     move the model much less (just a bit in vicinity of a local
>>     minimum) than any program that uses gradients only (like Phenix).
>     good point.
>
>     So, what should I do to stabilize phenix.geometry_minimization? 
>     Crank up the non-bonded weight?  Restrain to starting coordinates?
>
>>>     Files and logs here:
>>>     https://bl831.als.lbl.gov/~jamesh/bugreports/phenixmin_070721.tgz
>>>     <https://bl831.als.lbl.gov/~jamesh/bugreports/phenixmin_070721.tgz>
>>>
>>>     I suspect this might have something to do with library values
>>>     for main-chain bonds and angles?  They do seem to vary between
>>>     programs. Phenix having the shortest CA-CA distance by up to
>>>     0.08 A. After running thorough minimization on a poly-A peptide
>>>     I get:
>>>     bond   amber   refmac  phenix  shelxl Stryer
>>>      C-N   1.330   1.339   1.331   1.325     1.32
>>>      N-CA  1.462   1.482   1.455   1.454     1.47
>>>     CA-C   1.542   1.534   1.521   1.546     1.53
>>>     CA-CA  3.862   3.874 *3.794* 3.854
>>>
>>>     So, which one is "right" ?
>>
>>     I'd say they are all the same, within their 'sigmas' which are
>>     from memory about 0.02A:
>     I note that 3.874 - 3.794 = 0.08 > 0.02
>
>     This brings me to my pet theory.  I think what is going on is
>     small errors like this build up a considerable amount of tension
>     in the long main chain. For this 64-mer, the contour length of the
>     main chain after idealization is ~5 A shorter after
>     phenix.geometry_minimization than it is after shelxl or amber. 
>     That 5 A has to come from somewhere.  Without stretching bonds or
>     bending angles the only thing left to do is twisting torsions. A
>     kind of "whirlygig" effect.
>
>     The question is: is the phenix CA-CA distance too short?  Or is
>     the amber CA-CA distance too long?
>
>     Shall we vote?
>
>     -James
>
>
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