CCP4: Low resolution complexes; handling difficult data; empowering structural biologists and supporting UK structural biology
Lead Research Organisation:
University of York
Department Name: Chemistry
Abstract
Structural Biology is a powerful tool for analysing biological molecules. In essence it locates the atoms that make up proteins and other biomolecules. It is used in basic science to define the 3D structures of such molecules as the ribosome, ion channels and complex protein assemblies such as ATPase. Once a 3D 'model' of all the atoms in the biological model is available, it is possible to make deductions about how the molecule functions within the organism. This knowledge has corresponding applications in controlling that function, often leading to medical advances in drug design, better understanding of biological and feedback systems in the natural environment, new approaches in chemical engineering, and many other benefits. The process of 'solving' the structure involves first obtaining crystals and then exposing these to X-rays: this is equivalent to using a very powerful microscope and allows us to 'see' individual atoms. Getting crystals is in itself very demanding and involves a lot of skill and scientific insight. There is an additional problem in using X-rays in that there is no lens system for the microscope. This means that indirect, so-called diffraction images of the crystal are recorded. The process of extracting data from these images and proceeding to a final structure is computationally intensive and requires an entirely different set of skills from those of the biologist. Developing new computer methods and crucially embedding them in robust easy-to-use software will transform structural biology from a labour intensive highly technical process to a routine tool in biology. The main focus of this grant is on the computational process of solving 3D structures. CCP4 is a project which has collected, developed, packaged and distributed software for the many stages of this process, acting as a focus for methods development for over 25 years and making software available to both Academic and Industrial teams working in this area. It is an excellent example of technology transfer of basic science into a major UK Industry: Pharmaceutical development. The problem cannot yet be said to be totally solved. Biologists firstly are tackling more and more difficult structures, which require novel techniques. In addition, they are solving large number of sometimes related structures, such as a series of mutants and complexes, where automated high throughput is vital and systematic record keeping is essential. This proposal is focussed on enabling these developments.
Technical Summary
1. RA Post 1. Low resolution structures present special problems. Template-matching methods developed by Dr Cowtan provide a proven basis for the interpretation of maps of limited quality, and these methods will be enhanced by the use of larger scale structural information; this approach will be applied to model building and refinement at lower resolutions. 2. RA Post 2. Integrating intensities from diffraction images represents a crucial and fundamental step in the structure determination process, as all subsequent steps are dependent on these measurements and their estimated standard uncertainties. New data processing algorithms will be developed to handle multiple lattices, to automate processing and data analysis and to deal with the new Pilatus detectors. 3. RA Post 3. A database back-end will be developed to systematise and store all the data relevant to structure solution. We will design sensible 'wizards' to improve the consistency and accelerate the rate of structure determination, based on systematic handling of this information. 4. RA Post 4. Finally, for these tools to have the maximum benefit they will be translated into robust well-supported software distributed to the community. Software produced by tasks 1-3, by other CCP4 supported projects, and by independent contributors will be integrated into the suite in a way that is intuitive for a non-specialist. These major tasks will be complemented by suite-wide changes that keep CCP4 relevant to the latest challenges, such as large complexes.
Publications
Cowtan K
(2014)
Automated nucleic acid chain tracing in real time.
in IUCrJ
Potterton, L
(2012)
CCP4i2 for Programmers
Cowtan K
(2012)
Completion of autobuilt protein models using a database of protein fragments.
in Acta crystallographica. Section D, Biological crystallography
Emsley P
(2010)
Features and development of Coot.
in Acta crystallographica. Section D, Biological crystallography
Cowtan K
(2011)
From crystal to structure with CCP4.
in Acta crystallographica. Section D, Biological crystallography
Winn MD
(2011)
Overview of the CCP4 suite and current developments.
in Acta crystallographica. Section D, Biological crystallography
Description | We have developed software which can automatically work out the atomic structure (the shape and chemistry) of biological molecules, using data from X-ray crystallography experiments. The software performs a laborious and previously time consuming step of fitting atoms into an 'outline' of the electron density. Major advances were made in the improvement of automatically built protein models, especially with very limited starting data. In addition, new software has been developed for building nucleic acid models, and distributed through CCP4. |
Exploitation Route | The software we have developed has been incorporated in the CCP4 software suite, which is licensed by 100 industrial users worldwide as well as being used world-wide by academic laboratories. The nucleotide building code has also been incorporated in the 'Coot' software - this software as a whole is cited in approximately 3000 new papers each year. |
Sectors | Pharmaceuticals and Medical Biotechnology |
Description | The software we produced has been contributed to the CCP4 software suite, which sells ~100 commercial licences to pharmaceutical and biotech users, raising ~£1m/year. The software is used in the determination of the structure of biological molecules; this is a key step in the design of new drugs, and also has applications in biotechnology. |
Sector | Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | CCP4 Advanced integrated approaches to macromolecular structure determination |
Amount | £340,384 (GBP) |
Funding ID | BB/S005099/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2019 |
End | 03/2024 |
Description | CCP4 Grant Renewal 2014-2019: Question-driven crystallographic data |
Amount | £1,437,368 (GBP) |
Funding ID | BB/L006383/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2014 |
End | 03/2019 |
Title | Buccaneer version 1.6.0 protein model building software |
Description | Buccaneer is an automated protein model building program. It features robust handling of limited data resolution, and is competitive in terms of speed. It is particularly useful at resolutions of worse than 2.5A, although it can also be used at high resolution. |
Type Of Technology | Software |
Year Produced | 2014 |
Open Source License? | Yes |
Impact | 500+ citations, including many from the pharma/biotech sectors. Distribution as part of the CCP4 software suite to 100 commercial licensees. |
URL | http://www.ysbl.york.ac.uk/~cowtan/buccaneer/buccaneer.html |
Title | CCP4 i2 graphical user interface |
Description | CCP4i2 is a new user-oriented graphical user interface for the CCP4 software suite. It aims to restate the language of the crystallographic structure solution process in the language of the molecular biologist, rather than assuming a specialist background in crystallographic structure solution. The user interface scales to different levels of user expertise, and closely integrates graphical tools such as CCP4mg and Coot. |
Type Of Technology | Software |
Year Produced | 2014 |
Open Source License? | Yes |
Impact | None yet, still in alpha release. |
URL | https://fg.oisin.rc-harwell.ac.uk/scm/?group_id=92 |
Title | Nautilus nucleotide model building software |
Description | 'Nautilus' is a program for automatic model building of nucleotide structures in electron density maps. It will trace a map with no model, extend an existing model, or add nucleotide chains to an existing non-nucleotide model. |
Type Of Technology | Software |
Year Produced | 2011 |
Open Source License? | Yes |
Impact | Incorporation of Nautilus in the ubiquitous 'Coot' software brings it to an audience of 10,000+ users. Distribution as part of the CCP4 software suite to 100 commercial licensees. |
URL | http://www.ysbl.york.ac.uk/~cowtan/nautilus/nautilus.html |
Title | Nautilus nucleotide model building software - version 0.4 |
Description | 'Nautilus' is a program for automatic model building of nucleotide structures in electron density maps. It will trace a map with no model, extend an existing model, or add nucleotide chains to an existing non-nucleotide model. |
Type Of Technology | Software |
Year Produced | 2014 |
Open Source License? | Yes |
Impact | Incorporation of Nautilus in the ubiquitous 'Coot' software brings it to an audience of 10,000+ users. Distribution as part of the CCP4 software suite to 100 commercial licensees. |
URL | http://www.ysbl.york.ac.uk/~cowtan/nautilus/nautilus.html |
Description | CCP4 Study Weekend 2011 Kevin Douglas Cowtan - Invited speaker, 5 Jan 2011 |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Invited speaker on "Automated model building and refinment" |
Year(s) Of Engagement Activity | 2011 |
Description | CCP4 Study Weekend 2012 Kevin Douglas Cowtan - Invited speaker, 5 Jan 2012 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Invited speaker on "Nucleic Acid model building" |
Year(s) Of Engagement Activity | 2012 |
Description | CCP4 Study Weekend 2013 Kevin Douglas Cowtan - Invited speaker, 5 Jan 2013 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Invited talk on "Model free refinement" |
Year(s) Of Engagement Activity | 2013 |
URL | https://www.youtube.com/watch?v=EC0prOfPGKM |