May be this article is of some help suggesting the need of
experimental structures despite excellent alphafold model.
https://www.nature.com/articles/s41401-022-00938-y
------------------------------------------------------------------------
*From:* CCP4 bulletin board <[email protected]>
<mailto:[email protected]> on behalf of Ian Tickle
<[email protected]> <mailto:[email protected]>
*Sent:* Sunday, April 2, 2023 8:28 AM
*To:* [email protected] <[email protected]>
<mailto:[email protected]>
*Subject:* [External] Re: [ccp4bb] Structure prediction - waiting
to happen
All, the first hurdle will of course be whether the AlphaFold
model works as a MR model, even with the 100% completeness and
sequence identity of a bespoke model. The question is what B
factors to use or which disordered bits to leave out, as that can
strongly influence the result (perhaps use info from a similar
structure). If it doesn't work in MR that's a pretty good
indication that it's too far from reality to be useful for
looking at detailed interactions.
Does anyone know of a systematic investigation of the success
rate of AlphaFold models in MR ? That would be useful ammunition !
Cheers
-- Ian
On Sun, 2 Apr 2023 at 11:51, Gerard Bricogne
<[email protected]> wrote:
Dear all,
I think that quoting general viewpoints and statements,
however
knowledgeable and respected their authors may be, will only
exacerbate the
climate of clashing prejudices between two camps and is bound
to sustain a
war of opinions rather than lead to a rational acceptance
that something has
changed. The frustration is that one camp (the AlphaFold
believers) can be
viewed as in effect preventing experiments that could prove
it wrong.
One way to deal with this obstruction would be to
provide, in each
particular case, evidence that the AlphaFold results "do not
cut it" as the
sole provider of 3D information within the project at hand.
This means that
every grant proposal requesting resources towards a
crystallographic
structure solution should document the fact that AlphaFold
predictions have
been performed (or, often, looked up in a database of
pre-cooked results)
but do not provide the accuracy required for the proposed
investigation. If
this step of writing up the "Background" section of the grant
actually
delivers a useful result, then everyone will be happy; and if
it doesn't,
then the case for the need to allocate resources to solving
the structure by
crystallography will be unassailable. In this way, AlphaFold
will be a game
changer (we have known that since July 2021) but not a game
killer. Savvas
alluded to a similar approach, but it could be made a formal
requirement
acceptable to both proposers and reviewers, who would then
both be dealing
with the situation in a scientific rather than dogmatic manner.
With best wishes,
Gerard.
--
On Sat, Apr 01, 2023 at 06:54:33PM +0000, Goldman, Adrian wrote:
> I think this is all true - and I’ve been putting things
like this into my (failing) grants - but I get the
dispiriting sense that the medics think (to borrow a line
from hamlet) “the applicant doth protest too much methinks”.
>
> Well if as per James H today ;), we deposit coordinates to
1sf, alphafold will be just fine.
>
> Of course the coordinates won’t be of any use to anybody,
but the pictures will be nice.
>
> Adrian
>
> Sent from my iPhone
>
> > On 1 Apr 2023, at 21:39, Randy John Read
<[email protected]> wrote:
> >
> > There’s also this preprint with Tom Terwilliger as lead
author:
https://www.biorxiv.org/content/10.1101/2022.11.21.517405v1.
The title is “AlphaFold predictions: great hypotheses but no
match for experiment”.
> >
> > Best wishes,
> >
> > Randy
> >
> >> On 1 Apr 2023, at 18:18, Savvas Savvides
<[email protected]> wrote:
> >>
> >> Dear Rams,
> >>
> >> I salute you for sharing this.
> >>
> >> Just a week ago, I also received a remark along these
lines on a declined grant application. The remark was the
only unfavourable point, which suggested that it must have
weighed disproportionally towards the negative outcome. This
was a two-stage evaluation process and the grant was cut in
stage-1 where it was evaluated by a small group of
evaluators, none of whom was a structural
biologist/biochemist. Stage-2 would have involved peer review
by international experts.
> >>
> >> Despite my initial disbelief about what this remark
might have caused and upon reflection, I realized that it
might be time to become proactive in future applications in
anticipation of the apparent growing trend towards such
remarks and perceptions.
> >>
> >> I think that a generalized form of preemptive text might
not serve the purpose well, but perhaps well-articulated
statements specific to the proposed biological problem at
hand (perhaps aided by illustrations demonstrating the
inability of structure prediction to address the problem at
hand) might be the better way to go. Even though many of us
who teach courses in experimental structural biology and
structural bioinformatics at undergraduate and graduate
levels are already actively addressing many of these issues,
there is a much bigger and far more senior scientific
population out there that makes important decisions on
science
policy/funding/infrastructures/evaluations/recruitment/etc
that are not getting such educational exposure.
> >>
> >> The following resources provide good material and
starting points to reflect and elaborate upon.
> >>
> >> The article by Perrakis and Sixma in EMBO Reports
https://www.embopress.org/doi/full/10.15252/embr.202154046
> >>
> >> The recent comment paper in Nature Methods by Thomas Jane
> >> https://doi.org/10.1038/s41592-022-01760-4
> >>
> >> A correspondence in Science by Moore, Hendrickson,
Henderson and Brunger
> >>
https://www.science.org/doi/10.1126/science.abn9422?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
<https://www.science.org/doi/10.1126/science.abn9422?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed>
> >>
> >>
> >> Best wishes
> >> Savvas
> >>
> >>
> >> ----
> >> Savvas Savvides
> >> VIB Center for Inflammation Research
> >> Ghent University, Dept. of Biochemistry & Microbiology
> >> Technologiepark 71, 9052 Ghent, Belgium
> >>
> >> Email: [email protected] ;
[email protected]
> >> Phone: +32 (0)472 928 519 (mobile) ; +32 (0)9 331 36 60
(office)
> >> Web: https://savvideslab.sites.vib.be/en#/
> >>
> >>>> On 1 Apr 2023, at 16:57, Subramanian, Ramaswamy
<[email protected]> wrote:
> >>>
> >>> Ian,
> >>>
> >>> Thank you. This is not an April fools..
> >>> Rams
> >>> [email protected]
> >>>
> >>>
> >>>
> >>>> On Apr 1, 2023, at 10:46 AM, Ian Tickle
<[email protected]> wrote:
> >>>>
> >>>> ---- External Email: Use caution with attachments,
links, or sharing data ----
> >>>>
> >>>>
> >>>> Hi Ramaswamy
> >>>>
> >>>> I assume this is an April Fool's but it's still a
serious question because many reviewers who are not
crystallographers or electron microscopists may not fully
appreciate the difference currently between the precision of
structures obtained by experimental and predictive methods,
though the latter are certainly catching up. The answer of
course lies in the mean co-ordinate precision, related to the
map resolution.
> >>>>
> >>>> Quoting
https://people.cryst.bbk.ac.uk/~ubcg05m/precgrant.html :
> >>>>
> >>>> "The accuracy and precision required of an
experimentally determined model of a macromolecule depends on
the biological questions being asked of the structure.
Questions involving the overall fold of a protein, or its
topological similarity to other proteins, can be answered by
structures of fairly low precision such as those obtained
from very low resolution X-ray crystal diffraction data [or
AlphaFold]. Questions involving reaction mechanisms require
much greater accuracy and precision as obtained from
well-refined, high-resolution X-ray structures, including
proper statistical analyses of the standard uncertainties
(s.u.'s) of atomic positions and bond lengths.".
> >>>>
> >>>> According to
https://www.nature.com/articles/s41586-021-03819-2 :
> >>>>
> >>>> The accuracy of AlphaFold structures at the time of
writing (2021) was around 1.0 Ang. RMSD for main-chain and
1.5 Ang. RMSD for side-chain atoms and probably hasn't
changed much since. This is described as "highly accurate";
however this only means that AlphaFold's accuracy is much
higher in comparison with other prediction methods, not in
comparison with experimental methods. Also note that
AlphaFold's accuracy is estimated by comparison with the
X-ray structure which remains the "gold standard"; there's no
way (AFAIK) of independently assessing AlphaFold's accuracy
or precision.
> >>>>
> >>>> Quoting
https://scripts.iucr.org/cgi-bin/paper?S0907444998012645 :
> >>>>
> >>>> "Data of 0.94 A resolution for the 237-residue protein
concanavalin A are used in unrestrained and restrained
full-matrix inversions to provide standard uncertainties
sigma(r) for positions and sigma(l) for bond lengths.
sigma(r) is as small as 0.01 A for atoms with low Debye B
values but increases strongly with B."
> >>>>
> >>>> There's a yawning gap between 1.0 - 1.5 Ang. and 0.01
Ang.! Perhaps AlphaFold structures should be deposited using
James Holton's new PDB format (now that is an April Fool's !).
> >>>>
> >>>> One final suggestion for a reference in your grant
application:
https://www.biorxiv.org/content/10.1101/2022.03.08.483439v2 .
> >>>>
> >>>> Cheers
> >>>>
> >>>> -- Ian
> >>>>
> >>>>
> >>>> On Sat, 1 Apr 2023 at 13:06, Subramanian, Ramaswamy
<[email protected]> wrote:
> >>>> Dear All,
> >>>>
> >>>> I am unsure if all other groups will get it - but I am
sure this group will understand the frustration.
> >>>>
> >>>> My NIH grant did not get funded. A few genuine
comments - they make excellent sense. We will fix that.
> >>>>
> >>>> One major comment is, “Structures can be predicted by
alpfafold and other software accurately, so the effort put on
the grant to get structures by X-ray crystallography/cryo-EM
is not justified.”
> >>>>
> >>>> The problem is when a company with billions of $$s
develops a method and blasts it everywhere - the message is
so pervasive…
> >>>>
> >>>> Question: Is there a canned consensus paragraph that
one can add with references to grants with structural biology
(especially if the review group is not a structural biology
group) to say why the most modern structure prediction
programs are not a substitute for structural work?
> >>>>
> >>>> Thanks.
> >>>>
> >>>>
> >>>> Rams
> >>>> [email protected]
> >>>>
> >>>>
> >>>>
> >>>>
> >>>> To unsubscribe from the CCP4BB list, click the
following link:
> >>>>
https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1
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> >>>>
> >>>
> >>>
> >>> To unsubscribe from the CCP4BB list, click the
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> >>>
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> >>
> >>
> >> To unsubscribe from the CCP4BB list, click the following
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> >>
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> >>
> >
> > -----
> > Randy J. Read
> > Department of Haematology, University of Cambridge
> > Cambridge Institute for Medical Research Tel: +44 1223
336500
> > The Keith Peters Building
> > Hills Road E-mail: [email protected]
> > Cambridge CB2 0XY, U.K. www-structmed.cimr.cam.ac.uk
<http://www-structmed.cimr.cam.ac.uk>
> >
> >
> >
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