[phenixbb] phenix.polder - tool for calculating omit maps by excluding bulk solvent

Tim Gruene tim.gruene at psi.ch
Thu Apr 21 13:33:17 PDT 2016 

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Hi Pavel,

thank you, this is a very interesting and clear explanation!

Best wishes,
Tim

On Thursday, April 21, 2016 08:57:20 AM Pavel Afonine wrote:
> Hi Tim,
> 
> thanks for bringing this! Frankly I was not aware of SQUEEZE method
> likely because I'm not a heavy user of Platon. Anyways, this
> conversation prompted me to do some reading this morning:
> 
> http://journals.iucr.org/a/issues/1990/03/00/ge0049/ge0049.pdf
> http://scripts.iucr.org/cgi-bin/paper?S2053229614024929
> http://web.mit.edu/platon_v40505/platon/docs/platon/aca98.html
> 
> Here is what I gather from this. Well, first we are talking about
> small-molecule crystallography here, with all the implications. It may
> happen that crystals contain areas occupied by disordered solvent that
> is impractical to account for in terms of atomic model. I'm not an
> expert in small molecule crystallography but it sounds to me like this
> is something that rather does not happen all that often compared to
> bio-crystallography where the disordered (bulk) solvent typically
> occupies from 10 to 90% of the unit cell volume. Now, given high
> accuracy standards in small molecule crystallography this inability to
> account for disordered scattering poses a big problem as it hampers
> refinement and potentially highly accurate map interpretation. The
> SQUEEZE method provides a way to identify such regions of disordered
> scatterers and accounting for their contribution to the total model
> structure factors. For example, citing
> 
> A. L. Spek
> Acta Cryst. (2015). C71, 9-18
>   PLATON SQUEEZE: a tool for the calculation of the disordered solvent
> contribution to the calculated structure factors
> 
> """
> The completion of a crystal structure determination is often hampered by
> the presence of embedded solvent molecules or ions that are seriously
> disordered. Their contribution to the calculated structure factors in
> the least-squares refinement of a crystal structure has to be included
> in some way. Traditionally, an atomistic solvent disorder model is
> attempted. Such an approach is generally to be preferred, but it does
> not always lead to a satisfactory result and may even be impossible in
> cases where channels in the structure are filled with continuous
> electron density. This paper documents the SQUEEZE method as an
> alternative means of addressing the solvent disorder issue. It
> conveniently interfaces with the 2014 version of the least-squares
> refinement program SHELXL [Sheldrick (2015). Acta Cryst. C71. In the
> press] and other refinement programs that accept externally provided
> fixed contributions to the calculated structure factors. The PLATON
> SQUEEZE tool calculates the solvent contribution to the structure
> factors by back-Fourier transformation of the electron density found in
> the solvent-accessible region of a phase-optimized difference
> electron-density map. The actual least-squares structure refinement is
> delegated to, for example, SHELXL.
> """
> 
> Here is what we are dealing with in our case. Macro-molecular crystals
> on average contain ~50% of the disordered (bulk) solvent. Most (if not
> all) software packages automatically account for this disordered solvent
> by defining the total model structure factors as
> 
> Fmodel = k_total * (Fcalc_atoms + Fbulk) .
> 
> Fmodel is then used in all calculations such as R-factors, refinement
> targets, various maps, etc. Up to this point, it is along the lines of
> what SQUEEZE does, indeed.
> 
> Different bulk-solvent models can be used to calculate Fbulk
> contribution. Two major models are in use: Babinet-based model (used in
> SHELX) and Flat model (used in CNS, REFMAC, PHENIX).
> 
> Both models have their pros and cons. For example, the downside of
> Babinet-based model is that it holds true for resolutions lower than 10-15A:
> 
> Podjarny, A. D. & Urzhumtsev, A. G. (1997).
> http://www.ccp4.ac.uk/newsletters/newsletter38/08_solvent.html
> 
> and is handicapped at resolutions between 10-15 and 5-6A (where
> disordered solvent contribution vanishes). The good thing about it is
> that it does not implies masking bias.
> 
> Unlike Babinet model, Flat bulk-solvent model accounts for disordered
> solvent pretty well across all resolution ranges. The downside of the
> flat bulk solvent model is what we are trying to address using Polder maps.
> 
> So.. The way flat bulk solvent model works is it defines a solvent mask
> which is a binary function with 0 inside macro-molecule and 1 outside
> (Jiang&Brunger, 1997). Then this function is Fourier transformed into
> structure factors Fmask and that are then added to the total model
> structure factors with some refinable scale k_mask:
> 
> Fmodel = k_total * (Fcalc_atoms + k_mask * Fmask) .
> 
> The problem with this approach is that the solvent is "poured"
> everywhere in the unit cell where there is no atomic model. For example,
> if there is a ligand that is not placed yet or a loop that is not
> modeled yet, the flat bulk solvent will fill the gap. Most of the time
> this will not pose much trouble as atomic features typically stand above
> the noise or/and solvent density. However, in cases when feature that
> one tries to model is weak (mobile, partially occupied ligand or
> flexible disordered loop) the flat solvent model may obscure it by
> flattening corresponding density in the region of interest. This is the
> issue that Polder residual OMIT map is meant to address by excluding
> bulk-solvent contribution from specifically defined regions and
> therefore provide mask bias free view of residual map in that region. I
> think this is not quite the same as what SQUEEZE method does.
> 
> In fact Polded OMIT map is a single iteration of a more general
> procedure described in Section 2.4 and Figure 6 here:
> 
> http://journals.iucr.org/d/issues/2015/03/00/lv5075/lv5075.pdf
> 
> All the best,
> Pavel
> 
> On 4/21/16 06:21, Tim Gruene wrote:
> > Dear Dorothee,
> > 
> > With squeeze, you remove solvent in order to make features visible lying
> > underneath the noise density of the solvent. That's reminiscent to me as
> > the cartoon on p.9 of the phenix_polder.pdf
> > 
> > In Platon, the structure factors are calculated from the density in the
> > solvent region, Eq. (4) in the Platon paper. That appears to be the same
> > as
> > explained for phenix_polder on p. 4, except that phenix replaces
> > rho(x_solvent) with 1 for the mask. The equation on p.2 of the PDF-file is
> > identical to the line below Eq. 4 in the SQUEEZE paper, so it seems
> > conceptually pretty much the same to me.
> > 
> > Since SQUEEZE was presented at the ACA in 1998 (based on a paper from
> > 1990), I thought you may have been motivated by it. It is probably not
> > much surprising that good ideas get invented at various places.
> > 
> > Best wishes,
> > Tim
> > 
> > On Wednesday, April 20, 2016 01:59:34 PM you wrote:
> >> Hi Tim,
> >> 
> >> I quickly looked over the SQUEEZE command in PLATON (are you referring
> >> to:
> >> http://scripts.iucr.org/cgi-bin/paper?S2053229614024929 ?). To me, it
> >> does
> >> not seem to be related to phenix.polder.
> >> 
> >> There is no complicated math involved in polder; slides 2-4 are a summary
> >> of the flat bulk-solvent model (which is used in Phenix, and which is
> >> also
> >> available in CNS and REFMAC).
> >> 
> >> The flat bulk-solvent model is described first here:
> >> Phillips, S. E. (1980). *J. Mol. Biol.* *142*, 531–554.
> >> I uses a similar concept than SQUEEZE, i.e. the total structure factor is
> >> expressed as a sum of contributions from protein model and disordered
> >> solvent.
> >> 
> >> More references can be found in this review about bulk solvent models in
> >> MX: Weichenberger, C. X., Afonine, P. V, Kantardjieff, K. & Rupp, B.
> >> (2015). *Acta Crystallogr. Sect. D Biol. Crystallogr.* *71*, 1023–1038.
> >> 
> >> The polder tool uses the bulk solvent mask (as it is generated for other
> >> functionalities in phenix, such as phenix.refine), and then modifies the
> >> mask locally. I am sorry if the presentation file is misleading, I should
> >> maybe add some references to make clear what is summary and what is
> >> related
> >> to the polder tool.
> >> 
> >> Best wishes,
> >> 
> >> Dorothee
> >> 
> >> PS:
> >> I did not understand how the name "squeeze" relates to "polder"...
> >> 
> >> On Wed, Apr 20, 2016 at 12:07 PM, Tim Gruene <tim.gruene at psi.ch> wrote:
> >>> -----BEGIN PGP SIGNED MESSAGE-----
> >>> Hash: SHA1
> >>> 
> >>> Hi Pavel,
> >>> 
> >>> this is an interesting concept. It seems related to the SQUEEZE command
> >>> in
> >>> platon - even the name appears to suggest a relationship. I did not
> >>> understand
> >>> the maths entirely: Are they similar concept, or do I misinterprete?
> >>> 
> >>> Best,
> >>> Tim
> >>> 
> >>> On Wednesday, April 20, 2016 07:28:16 AM Pavel Afonine wrote:
> >>>> Hello,
> >>>> 
> >>>> it's good to know it was useful for you, thanks for feedback! I afraid
> >>>> it's too new so that we don't have a publication to cite yet. We are
> >>>> working on a manuscript but it may take a little while before it
> >>>> appears
> >>>> somewhere. For now I guess you can use this link (unless Dorothee has a
> >>>> better idea)
> >>>> 
> >>>> http://www.phenix-online.org/presentations/phenix_polder.pdf
> >>>> 
> >>>> and use official Phenix citation:
> >>>> 
> >>>> Acta Cryst. D66, 213-221 (2010).
> >>>> 
> >>>> That's all we have at the moment anyway.
> >>>> 
> >>>> All the best,
> >>>> Pavel
> >>>> 
> >>>> On 4/20/16 04:18, Lund Bjarte Aarmo wrote:
> >>>>> DearDorothee and phenixbb,
> >>>>> 
> >>>>> I found this software very useful for protein-fragment complexes with
> >>>>> weak electron density. I was wondering how the software should be
> >>> 
> >>> cited?
> >>> 
> >>>>> Kind regards,
> >>>>> 
> >>>>> Bjarte Aarmo Lund
> >>>>> 
> >>>>> PhD candidate
> >>>>> 
> >>>>> UiT – The arctic university of Norway
> >>>>> 
> >>>>> *From:*phenixbb-bounces at phenix-online.org
> >>>>> [mailto:phenixbb-bounces at phenix-online.org] *On Behalf Of *Dorothee
> >>>>> Liebschner
> >>>>> *Sent:* 22. mars 2016 21:46
> >>>>> *To:* PHENIX user mailing list <phenixbb at phenix-online.org>
> >>>>> *Subject:* [phenixbb] phenix.polder - tool for calculating omit maps
> >>>>> by excluding bulk solvent
> >>>>> 
> >>>>> Dear phenix users,
> >>>>> 
> >>>>> Starting from the nightly build dev-2356, a new tool for calculating
> >>>>> ligand omit-maps, called 'polder', is included in phenix.
> >>>>> 
> >>>>> Usage:
> >>>>> 
> >>>>> phenix.polder model.pdb    data.mtz    selection='chain A and resseq
> >>> 
> >>> 123’
> >>> 
> >>>>> Phenix.polder calculates omit maps for atom selections by preventing
> >>>>> the bulk solvent mask to flood into the atom selection area and its
> >>>>> vicinity. The tool can be useful in cases where the density of the
> >>>>> selected atoms is weak and possibly obscured by bulk solvent.
> >>>>> 
> >>>>> Polder produces less biased maps compared to procedures where the atom
> >>>>> selection occupancy is set to zero, and the atoms are included in the
> >>>>> solvent mask calculation (in that case, the resulting difference
> >>>>> density can have similar shape than the selected atoms). Phenix.polder
> >>>>> excludes a larger volume from the bulk solvent and therefore prevents
> >>>>> misinterpreting bulk solvent density as omit density.
> >>>>> 
> >>>>> If you want to know more about how the tool is working and to see some
> >>>>> examples, have a look at the presentation file:
> >>>>> https://www.phenix-online.org/presentations/phenix_polder.pdf.
> >>>>> 
> >>>>> The documentation page can be found here:
> >>>>> 
> >>>>> www.phenix-online.org/version_docs/dev-2356/reference/polder.html
> >>>>> 
> >>>>> Best wishes,
> >>>>> 
> >>>>> Dorothee
> >>>>> 
> >>>>> 
> >>>>> 
> >>>>> _______________________________________________
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> >>>>> phenixbb at phenix-online.org
> >>>>> http://phenix-online.org/mailman/listinfo/phenixbb
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> >>> 
> >>> - --
> >>> - --
> >>> Paul Scherrer Institut
> >>> Tim Gruene
> >>> - - persoenlich -
> >>> OFLC/102
> >>> CH-5232 Villigen PSI
> >>> phone: +41 (0)56 310 5297
> >>> 
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Paul Scherrer Institut
Tim Gruene
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OFLC/102
CH-5232 Villigen PSI
phone: +41 (0)56 310 5297

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