Re: [ccp4bb] Structure prediction - waiting to happen

[James Holton]

Very sorry to hear about your grant. I've been there. It is crushing to 
be rejected, and frustrating when the reason given is ... wrong.


My journalist friends wonder why scientists don't like talking to 
journalists. This is why.  I remember when the first results from XFELs 
were published, and it was immediately declared that there was no longer 
a need for NASA, whose sole purpose (apparently) was to grow bigger and 
better crystals in space. (?!) I find the idea that AlphaFold has 
eliminated the need to solve any more structures equally ludicrous.


I think the best analogy for what has happened in structural biology is 
the same impact a Star Trek style "transporter device" would have on 
your daily commute. Except this "transporter" is only accurate enough to 
get you within a mile or two of your house.  Most of the time. Don't 
worry, its not going to beam you inside a rock or into the sky, as it 
was trained on data with good Clashscores (we think). But, you are on 
your own getting the rest of the way home. This "Last Mile" of 
transportation networks is actually the most challenging, and expensive, 
but also the most critical. In structural biology, the "Last Angstrom" 
between prediction and actuality is equally important, but also fraught 
with difficulty. It may seem like a short distance, until you have to 
walk it. So, despite amazing progress, it is still premature to 
dismantle infrastructure, and definitely a bad idea to nail your front 
door shut.


Personally, I see this structure prediction revolution as nothing more 
nor less than the fruition of Structural Genomics. It started in the 
final days of the 20th century. I was there! The stated goal of that 
worldwide initiative was to create the data set that would be needed by 
some future (at the time) homology modelling technology to do exactly 
what AlphaFold does: get us "close enough".  And then Greg Petsko asked: 
what is "close enough"?  He called it "The Grail problem". By what 
metric do you declare victory?  He made an excellent suggestion:


"But there is an obvious method of evaluation that will allow any 
structure prediction method to be assessed. It is simply to demand that 
the method produce a model that can be used to solve the corresponding 
protein crystal structure by the method of molecular replacement."

-Greg Petsko - June 9, 2000
https://doi.org/10.1186/gb-2000-1-1-comment002

This is the thing that just changed.  Structure prediction has finally 
crossed the "G-P threshold". Not 100% of the time, but impressively 
often now, the predictions can be used for MR. This is a massively 
useful tool!  Not the end of the field, but rather the beginning of an 
exciting new era where success rates skyrocket.


Scores like the GDT used in CASP were developed with this Grail Problem 
criterion in mind, and I think that is what John Moult and others meant 
when they said things that got quoted like this:
"Scores above 90 on the 100-point scale are considered on par with 
experimental methods, Moult says."

https://www.science.org/doi/full/10.1126/science.370.6521.1144

Meaning that the predicted models work as search models for MR about as 
often as search models derived from homologous (and yes, "experimentally 
determined") structures.  A GDT of 100 does NOT mean the model is better 
than the data. That is not even how it works.


But, unfortunately, this seems to have gotten paraphrased and 
sensationalized:


"generally considered to be competitive with the same results obtained 
via experimental methods"

https://www.sciencealert.com/ai-solves-50-year-old-biology-grand-challenge-decades-before-experts-predicted

"software predictions finally match structures calculated from 
experimental data"

https://www.science.org/doi/full/10.1126/science.370.6521.1144

"comparable in quality to experimental structures"
https://www.nature.com/articles/d41586-020-03348-4

"accuracy comparable to laboratory experiments"
https://www.bbc.com/news/science-environment-55133972



The only kind of diffraction where prediction is better than experiment 
is that of monoatomic gasses. These curves can be derived very 
accurately and completely from fundamental constants of physics. This is 
where those tables of atomic scattering factors used by refinement 
programs come from. For a while, the experimentally measured curves were 
used, but once Hartree, Fock, Slater, Cromer, Mann and others worked out 
how to do the self-consistent field calculations accurately, by the late 
1960s the calculated form factors supplanted the measured ones.


You might also say that for "small molecule" crystals the models are 
better than the data. Indeed, the CSD did not require experimental data 
to be deposited until fairly recently.  The coordinates were considered 
more accurate than the intensities because publication requirements for 
chemical crystallography R factors are low enough to be dominated by 
experimental noise only.  Nevertheless, 

[ccp4bb] Postdoc position in San Antonio, TX

[Yogesh Gupta]

*NIH-funded Postdoctoral Associate position in Structural Virology at the
University of Texas Health Science Center, San Antonio*

The laboratory of Dr. Yogesh Gupta (http://ccri.uthscsa.edu/YGupta.html) is
seeking an enthusiastic Postdoctoral Associate to study the structures and
specificity of RNA modification enzymes. We will mainly use X-ray
crystallography and cryo-EM to study the mechanisms and develop small
molecule antiviral candidates. We provide a rich multi-disciplinary
environment and access to cutting-edge technologies to our trainees.



Further details of our recent work can be found here:

Elife. 2022 Jan 21;11:e67150. doi: 10.7554/eLife.67150
.

Nature Communications. 2021 Jun 2; 12: 3287. PMID: 34078893. doi:
10.1038/s41467-021-23594-y


Nature Communications. 2020 Jul 24;11(1):3718. PMID: 32709886. doi:
10.1038/s41467-020-17496-8




Preference will be given to applicants with demonstrated experience in
protein purification from insect or mammalian cells, protein/nucleic acid
biochemistry, X-ray crystallography, and cryo-EM. Candidates are expected
to possess strong organizational and interpersonal skills and the ability
to work independently but also effectively and collaboratively as part of a
team. An ideal candidate should hold (or soon expect to) a Ph.D. or
equivalent degree in biochemistry/biophysics/structural biology.



The Greehey Children’s Cancer Research Institute (GCCRI) is a unique,
specialized cancer research center of UT Health Science Center San Antonio,
focusing on basic and translational research. It occupies a
state-of-the-art 100,000 sq. foot research facility on the university’s
Greehey Academic and Research Campus. The GCCRI has significant external
funding, a large endowment from the state, and links to philanthropic
entities. San Antonio is the nation’s seventh-largest city and is located
at the edge of the beautiful Texas Hill Country. San Antonio offers a rich,
multicultural community, affordable cost of living, excellent weather, and
a thriving biomedical industry. There is no state income tax in Texas.
Salary is competitive and commensurate with experience.



Interested candidates can apply by sending a short description of their
research accomplishments and a CV with the contact information of 3
references to Dr. Yogesh Gupta (email: gup...@uthscsa.edu).



*All Postdoctoral appointments are designated as security-sensitive
positions. UT Health San Antonio is an Equal Opportunity/Affirmative Action
Employer, including protected veterans and persons with disabilities.*


-- 
Yogesh Gupta, Ph.D.
Associate Professor
Department of Biochemistry and Structural Biology
University of Texas Health Science Center at San Antonio
8403 Floyd Curl Drive, San Antonio, TX, USA 78229
http://ccri.uthscsa.edu/YGupta.html



To unsubscribe from the CCP4BB list, click the following link:
https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB=1

This message was issued to members of www.jiscmail.ac.uk/CCP4BB, a mailing list 
hosted by www.jiscmail.ac.uk, terms & conditions are available at 
https://www.jiscmail.ac.uk/policyandsecurity/

[ccp4bb] Université Paris-Saclay - Postdoctoral researcher position

[Olivier Berteau]

Dear Crystallography Community,

We are seeking for a highly motivated post-doctoral researcher to join 
the ChemSyBio lab at the Micalis institute 
 (Université Paris-Saclay 
), located in Jouy-en-Josas 
near Paris. The position is funded for up to two years.


The research project is focused on the mechanistic and structural 
investigation of novel metalloenzymes and will combine several 
structural biology approaches (X-ray crystallography, SAXS, Cryo-EM). 
The candidate should have a a PhD in biochemistry, structural biology or 
related field. Experience in protein structure determination and protein 
expression/purification is a plus.


Our institute provides a vibrant and international environment for 
researchers interested in interdisciplinary research with access to 
state-of the art synchrotron radiation facilities.


Selected publications from our lab:
- Fyfe et al., 2022 Nature, 602(7896):336-342.
- Parent et al., 2018 J Am Chem Soc. ; 140(7):2469-2477
- Benjdia et al., 2017 Nature Chemistry ; 9(7):698-707
- Parent et al., 2016 J Am Chem Soc.; 138(48):15515-15518
- Benjdia et al. 2015 Nat Commun. 12;6:8377

Applications (including CV and reference letters) should be sent to Dr 
Olivier Berteau (olivier.bert...@inrae.fr) and Dr Alhosna Benjdia 
(alhosna.benj...@inrae.fr).


Best wishes,

Olivier

--


*Dr. Olivier BERTEAU*

/INRAE, Université Paris-Saclay/

/UMR1319 MICALIS, ChemSyBio/

78350 Jouy en Josas cedex, France – phone : +33 (0)1 34 65 23 08

_http://www.micalis.fr_



To unsubscribe from the CCP4BB list, click the following link:
https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB=1

This message was issued to members of www.jiscmail.ac.uk/CCP4BB, a mailing list 
hosted by www.jiscmail.ac.uk, terms & conditions are available at 
https://www.jiscmail.ac.uk/policyandsecurity/

[ccp4bb] CCPBioSim Industry Talk - Rescheduled

[Sarah Fegan - STFC UKRI]

Dear all,

The Industry Talk has been rescheduled, it will now be on Wednesday 26 April 
2023 at 3 pm UK time. If you had already registered, your registration will 
still be valid for the new date. The speaker is Alexander D. MacKerell and the 
title is "Introduction to Site Identification by Ligand Competitive Saturation 
(SILCS) and its Application in Drug Design and Development." Details and 
registration at https://www.ccpbiosim.ac.uk/silcs2023.

Abstract: SILCS involves generating a pre-computed ensemble of 1) the 
distribution of solutes and water in the full 3D space of proteins or RNA as 
well as 2) the conformations of the macromolecule using combined oscillating 
excess chemical potential Grand-Canonical Monte Carlo/Molecular Dynamics 
simulations. From the precomputed ensemble 3D "FragMaps" are produced that 
represent functional group free energies relative to aqueous solution in the 
full 3D space of the macromolecular system.  The free energies include 
contributions on macromolecular flexibility, desolvation of the functional 
groups and the macromolecule and functional group-macromolecular interactions.  
Once precomputed the SILCS FragMaps may be used for a variety of free energy 
related calculations in a highly computationally accessible manner.  These 
include binding affinities of fragments and drug-like molecules, generation of 
pharmacophores, and lead compound optimization. In addition, FragMaps may be 
utilized for calculation of protein-protein interactions, glycan-protein 
interactions, and the full distributions of ligands in the 3D space of 
macromolecules for use in allosteric binding site identification, 
fragment-based drug design, and the rational design of excipients for biologics 
drugs formulation.  In addition, the SILCS methodology may be applied to 
membranes allowing for investigations of the partitioning of molecules in 
interfacial systems and prediction of permeabilities in conjunction with 
artificial intelligence.  An introduction to the SILCS technology and details 
of various applications will be presented.

Best wishes,
Sarah



To unsubscribe from the CCP4BB list, click the following link:
https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB=1

This message was issued to members of www.jiscmail.ac.uk/CCP4BB, a mailing list 
hosted by www.jiscmail.ac.uk, terms & conditions are available at 
https://www.jiscmail.ac.uk/policyandsecurity/

[ccp4bb] Obituary for Alexei Vagin for those who are interested

[Eleanor Dodson]

>From Louise Jones - Acta cryst editor

We put together an obituary for Alexei with contributions from his friends
and colleagues in Moscow and the UK

L*ouse says: I am hoping to put the obituary online this afternoon.*

*The page numbers have not yet been assigned but it can be cited with the*
*doi: Dodson, E. (2023). Acta Cryst. D79,*
https://doi.org/10.1107/S2059798323003364.
*The page numbers will be available at the end of the month.*

Best wishes
Louise



To unsubscribe from the CCP4BB list, click the following link:
https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB=1

This message was issued to members of www.jiscmail.ac.uk/CCP4BB, a mailing list 
hosted by www.jiscmail.ac.uk, terms & conditions are available at 
https://www.jiscmail.ac.uk/policyandsecurity/