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]> on behalf of Ian
Tickle <[email protected]>
*Sent:* Sunday, April 2, 2023 8:28 AM
*To:* [email protected] <[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:
> >>>>
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> >>>>
> >>>
> >>>
> >>> To unsubscribe from the CCP4BB list, click the following link:
> >>>
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> >>
> >>
> >> To unsubscribe from the CCP4BB list, click the following link:
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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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