Bioinformatics Resources for Circular Dichroism Spectroscopy and Structural Biology: Operation, Enhancement, Curation, and New Developments
Lead Research Organisation:
Birkbeck, University of London
Department Name: Biological Sciences
Abstract
This proposal is for a renewal of the previously-funded Bioinformatics and Biological Resources Fund project "The Protein Circular Dichroism Data Bank, the DichroWeb Server, and ValiDichro: Data Sharing, Analysis and Standards Resources for CD Spectroscopy", which enabled the creation, curation, operation and development of the unique Protein Circular Dichroism Data Bank (PCDDB) for free public data-sharing of spectroscopic and meta-data, DichroWeb, the most widely-used resource (in the UK and internationally) for analysis of CD spectra, and the advancement of data quality standards and validation protocols.
This project's aims are to operate, curate, enhance, and maintain these comprehensive electronic archiving and analysis resources for CD spectroscopy which are widely used by both the academic and commercial (bigPharma, SMEs, food industry) sectors in the life sciences. It also aims to develop new analysis tools for structural biology, and to promote data-sharing, including the reuse and re-purposing of archived data. This will maximise public benefit from data generated by UK research council-funded studies. The project would also support the development of a new suite of tools for novel types of analyses (including cross-methodological ones), and a "one-stop-shop" server providing a pipeline for processing, analysis, display, and data bank deposition (thereby simplifying and improving the use of CD spectroscopy by the non-expert community, and the speeding up of these processes for regular CD users). An added value for the resources is that they are used in teaching undergraduate and graduate students, and through workshops, videos, publications, and user training sessions, we will provide educational as well as operational tools. These projects have strong support from both the UK and international user communities, as indicated by the letters of support included with the proposal.
In summary, these bioinformatics and data-sharing resources provide a comprehensive package of enabling and supportive tools in CD spectroscopy for academic and industrial biochemists, structural biologist, and bioinformaticists.
This project's aims are to operate, curate, enhance, and maintain these comprehensive electronic archiving and analysis resources for CD spectroscopy which are widely used by both the academic and commercial (bigPharma, SMEs, food industry) sectors in the life sciences. It also aims to develop new analysis tools for structural biology, and to promote data-sharing, including the reuse and re-purposing of archived data. This will maximise public benefit from data generated by UK research council-funded studies. The project would also support the development of a new suite of tools for novel types of analyses (including cross-methodological ones), and a "one-stop-shop" server providing a pipeline for processing, analysis, display, and data bank deposition (thereby simplifying and improving the use of CD spectroscopy by the non-expert community, and the speeding up of these processes for regular CD users). An added value for the resources is that they are used in teaching undergraduate and graduate students, and through workshops, videos, publications, and user training sessions, we will provide educational as well as operational tools. These projects have strong support from both the UK and international user communities, as indicated by the letters of support included with the proposal.
In summary, these bioinformatics and data-sharing resources provide a comprehensive package of enabling and supportive tools in CD spectroscopy for academic and industrial biochemists, structural biologist, and bioinformaticists.
Technical Summary
Circular Dichroism (CD) spectroscopy is a technique that is widely used in biochemistry, structural biology, and biophysics for determining protein secondary structures, detecting conformational changes, and examining macromolecular interactions and protein folding, and is a method designated by international regulatory agencies for characterisation of pharmaceutical proteins.
This proposal is to operate, maintain, curate, and enhance a comprehensive set of electronic archiving and analysis resources for CD spectroscopy. It is a renewal/follow-on application for a BBR grant that enabled creation and development of bioinformatics resources for data-sharing and analysis of CD spectroscopic data, and for inter-operability tools relating CD spectroscopy, crystallography and NMR spectroscopy.
It includes the Protein Circular Dichroism Data Bank (PCDDB), a deposition, searchable and downloadable data bank of CD spectra which provides public archiving facilities and open access to validated CD spectral and meta-data, DichroWeb, the most widely-used online server for the analysis of CD data; the CDTools data processing, analysis and display software; 2Struc, for secondary structure calculations and displays based on coordinate data from crystallography and NMR; PDB2CD for calculating CD spectra based on 3D structures; and DichroMatch, for identifying close spectral neighbours for use in structural and functional studies. New developments will include enhancements to all of these, and new tools such as an online pipeline facility to simplify data processing, validation, analysis, display, and data-sharing (aiding casual users as well as improving throughput for more advanced users), tools for quantitative spectral comparisons (with applications in bioprocessing), and for analyses of oriented CD spectra. Finally, it will include extensive user liaison and training facilities, and outreach in the area of data-sharing.
This proposal is to operate, maintain, curate, and enhance a comprehensive set of electronic archiving and analysis resources for CD spectroscopy. It is a renewal/follow-on application for a BBR grant that enabled creation and development of bioinformatics resources for data-sharing and analysis of CD spectroscopic data, and for inter-operability tools relating CD spectroscopy, crystallography and NMR spectroscopy.
It includes the Protein Circular Dichroism Data Bank (PCDDB), a deposition, searchable and downloadable data bank of CD spectra which provides public archiving facilities and open access to validated CD spectral and meta-data, DichroWeb, the most widely-used online server for the analysis of CD data; the CDTools data processing, analysis and display software; 2Struc, for secondary structure calculations and displays based on coordinate data from crystallography and NMR; PDB2CD for calculating CD spectra based on 3D structures; and DichroMatch, for identifying close spectral neighbours for use in structural and functional studies. New developments will include enhancements to all of these, and new tools such as an online pipeline facility to simplify data processing, validation, analysis, display, and data-sharing (aiding casual users as well as improving throughput for more advanced users), tools for quantitative spectral comparisons (with applications in bioprocessing), and for analyses of oriented CD spectra. Finally, it will include extensive user liaison and training facilities, and outreach in the area of data-sharing.
Planned Impact
Circular dichroism (CD) spectroscopy is a widely-used technique in biochemistry and structural biology, for studying protein structures, folding, and conformational changes associated with different conditions, environmental effects, and drug binding. This proposal is for renewal of an existing BBR grant to enable future provision, operation, maintenance, enhancement, and development of a series of existing and new tools and resources for data-sharing and analyses of CD spectral data. The widely-used resources described in this proposal will continue to benefit a broad base of scientists who utilise CD spectroscopy in both academia and the commercial sector, and new tools will be developed to extract and utilise additional information from CD data.
CD spectroscopy is a method that is regularly used in academia to characterise proteins and other biomacromolecues, often in conjunction with methods such as crystallography and NMR spectroscopy. It is also a spectroscopic technique which meets ICH (International Council for Harmonisation of Technical Requirements) for characterisation of pharmaceuticals for human use, so there has also been significant interest by the pharmaceutical industry in the tools described in this proposal.
The Protein Circular Dichroism Data Bank (PCDDB) has already become a well-used resource for protein spectra and metadata and is a traceable resource for documentation of medicinal proteins (for bioprocessing and biosimilars comparisons), a means of fulfilling research council and publication requirements for data-sharing, and provides a freely-available means for re-use and re-purposing of existing data. The analysis, validation, spectral comparison and other tools to be enhanced, augmented and developed in this project will have value in protein characterisations and quality evaluations, and thereby support and enhance research in the wider science base.
The long-established DichroWeb analysis server [which was cited as an early example of impact in the RCUK "Study on the Economic Impact of the Research Councils"], is continually updated and enhanced, and has a proven record of widespread use in academia and by big pharma, SMEs and the food industry. This and our other existing resources have also proven to be valuable teaching tools in undergraduate and postgraduate programmes, and our user liaison, media, and training activities provide unique resources to the scientific community, thereby enhancing the skills base of the UK. It is thus expected that the resources in this project will continue to provide means of characterising, sharing and enhancing the utility of existing data, and provide new means of quality control and novel analyses for future characterisations of proteins and other biomacromolecules by both the academic and commercial sectors.
CD spectroscopy is a method that is regularly used in academia to characterise proteins and other biomacromolecues, often in conjunction with methods such as crystallography and NMR spectroscopy. It is also a spectroscopic technique which meets ICH (International Council for Harmonisation of Technical Requirements) for characterisation of pharmaceuticals for human use, so there has also been significant interest by the pharmaceutical industry in the tools described in this proposal.
The Protein Circular Dichroism Data Bank (PCDDB) has already become a well-used resource for protein spectra and metadata and is a traceable resource for documentation of medicinal proteins (for bioprocessing and biosimilars comparisons), a means of fulfilling research council and publication requirements for data-sharing, and provides a freely-available means for re-use and re-purposing of existing data. The analysis, validation, spectral comparison and other tools to be enhanced, augmented and developed in this project will have value in protein characterisations and quality evaluations, and thereby support and enhance research in the wider science base.
The long-established DichroWeb analysis server [which was cited as an early example of impact in the RCUK "Study on the Economic Impact of the Research Councils"], is continually updated and enhanced, and has a proven record of widespread use in academia and by big pharma, SMEs and the food industry. This and our other existing resources have also proven to be valuable teaching tools in undergraduate and postgraduate programmes, and our user liaison, media, and training activities provide unique resources to the scientific community, thereby enhancing the skills base of the UK. It is thus expected that the resources in this project will continue to provide means of characterising, sharing and enhancing the utility of existing data, and provide new means of quality control and novel analyses for future characterisations of proteins and other biomacromolecules by both the academic and commercial sectors.
Publications
Zanatta, G.
(2019)
Valproic Acid Interactions with the NavMs Voltage-Gated Sodium Channel
in Proceedings of the National Academy (USA)
Wallace Bonnie A.
(2020)
Tools and Resources for Circular Dichroism Spectroscopy
in BIOPHYSICAL JOURNAL
Wallace BA
(2019)
The role of circular dichroism spectroscopy in the era of integrative structural biology.
in Current opinion in structural biology
Wallace B
(2020)
Tools and Resources for Circular Dichroism Spectroscopy
in Biophysical Journal
Tolchard J
(2018)
The intrinsically disordered Tarp protein from chlamydia binds actin with a partially preformed helix.
in Scientific reports
Sait LG
(2020)
Cannabidiol interactions with voltage-gated sodium channels.
in eLife
Ramalli SG
(2022)
The PCDDB (Protein Circular Dichroism Data Bank): A Bioinformatics Resource for Protein Characterisations and Methods Development.
in Journal of molecular biology
Miles AJ
(2021)
Tools and methods for circular dichroism spectroscopy of proteins: a tutorial review.
in Chemical Society reviews
Miles AJ
(2018)
CDtoolX, a downloadable software package for processing and analyses of circular dichroism spectroscopic data.
in Protein science : a publication of the Protein Society
Description | developed and distributed new tools and software to academic and industrial labs that have been used for research and teaching of biophysics in a large number of UK Universities, companies, and by international researchers. one, the online CDWEb site has now been used by well over 1 million analyses by UK and international users, including academic research, PhD student and postdoc training, and pharmaceutical companies. new tools have been published and software lodged in Github and on websites for use by researchers after the grant has been completed and the postdoc/researcher have left |
Exploitation Route | already greatly used by many other groups nationally and internationally for research, and during covid it had many more new researchers use it when they couldnt collect more data but wanted to reanalyse previous datas, and it has been used for in silico teaching during covid by UK and other universities internationally, especially during lockdown |
Sectors | Agriculture, Food and Drink,Education,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
URL | http://dichroweb.cryst.bbk.ac.uk/html/home.shtml |
Description | tools and resources have been used by researchers in labs in industry as well as academia, and have been used for classroom teaching in UK and international universities. One resource alone (dichroweb|) currently has 7500+ registered users, who have performed > 1 milllion analyses |
First Year Of Impact | 2020 |
Sector | Agriculture, Food and Drink,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | Biophysical studies of the structure/function of antimicrobial peptides and enzymes isolated from extremophile organisms |
Amount | £35,426 (GBP) |
Funding ID | BB/N012763/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2016 |
End | 10/2018 |
Title | Dichroweb analysis website |
Description | software highly used by academic and industrial labs |
Type Of Material | Improvements to research infrastructure |
Provided To Others? | Yes |
Impact | high usage by academic labs, universities for teaching, and industrial labs |
URL | http://dichroweb.cryst.bbk.ac.uk/html/home.shtml |
Title | PCDDB |
Description | data bank for validated circular dichroism spectra |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2014 |
Provided To Others? | Yes |
Impact | more than 500,000 downloads already |
URL | http://pcddb.cryst.bbk.ac.uk |
Title | Validichro |
Description | server for validation of circular dichroism spectra |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2013 |
Provided To Others? | Yes |
Impact | used thousands of times by outside users |
URL | http://pcddb.cryst.bbk.ac.uk/home.php |
Title | design of a new SRCD beamline for Sirius synchtrotron in Brazil |
Description | design of a new SRCD beamline to be built at the Sirius synchrotron in Brazil |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | further collaborations and new collaboration grant between UK and Brazil |
Title | new software tools for CD analyses |
Description | software and websites and you tube videos about new infrastructure tools developed for CD spectroscopy and structural biology |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | ongoing development of many new tools for bioinformatics and structural biology resources widespread usage of tools both in the UK and internationally |
Title | oriented circular dichroism spectroscopy - methods development and software analysis tools |
Description | development of methodology and software analysis tools for oriented CD spectroscopy |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | other research groups interested in/using our Anglerfish server |
URL | http://anglerfish.cryst.bbk.ac.uk/ |
Title | Protein Circular Dichroism Data Bank |
Description | user deposition of spectral and meta data obtained circular dichroism of proteins |
Type Of Material | Database/Collection of data |
Year Produced | 2016 |
Provided To Others? | Yes |
Impact | more than 2M downloads of contents used by industry and academia led to the development of new methodologies by us and others |
Title | The MSP180 Reference Data Set |
Description | reference data set for the analysis of membrane protein circular dichroism spectra |
Type Of Material | Database/Collection of data |
Year Produced | 2011 |
Provided To Others? | No |
Impact | No actual impacts realised to date |
URL | http://pcddb.cryst.bbk.ac.uk/home.php |
Title | The SP175 reference Data Set |
Description | Data Set of Reference CD spectra of proteins deposited in the Protein Circular Dichroism Data Bank. protein circular dichoism data bank http://pcddb.cryst.bbk.ac.uk/home.php |
Type Of Material | Database/Collection of data |
Year Produced | 2009 |
Provided To Others? | No |
Impact | No actual impacts realised to date |
URL | http://pcddb.cryst.bbk.ac.uk/home.php |
Title | curartion and development of data base of circular dichroism spectroscopy and links to other bioinformatics resources |
Description | updated and expanded database and cross-referencing with other data bases such as PDB, Uniprot |
Type Of Material | Database/Collection of data |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | MANY downloads ((>1,000,000 files) by many research groups around the world |
Description | Collaboration on Intrinsically disordered proteins |
Organisation | Institute of Cancer Research UK |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Biophysical Studies on intrinsically disordered proteins Circular Dichroism Spectroscopy of intrinsically disordered protein |
Collaborator Contribution | Bioinformatics of Intrinsically disordered proteins |
Impact | Publication in F1000REs 2019 |
Start Year | 2018 |
Description | Partnership with International ELIXER group on intrinsically disordered proteins |
Organisation | ELIXIR |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | We provided the expertise in using CD spectroscopy to study intrinsically disordered proteins, as part of a large international group of biophysicists and bioinformaticists |
Collaborator Contribution | Links in our Protein Circular Dichroism Databank to other (international) groups and websites |
Impact | inter-database international links on a wide-ranging project defining Intrinsically Disordered Proteins and part of the Google Databases project |
Start Year | 2019 |
Description | collaboration with Janes Lab (Queen Mary University of London) |
Organisation | Queen Mary University of London |
Department | School of Biological and Chemical Science QMUL |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | a wide range of common outcomes, including publications, workshops, international talks |
Collaborator Contribution | a wide range of common outcomes, including publications, workshops, international talks |
Impact | publications, outreach, software, video (You Tube) instruction mannuals, teaching at international workshops, presentations at international meetings |
Description | collaborations with CD users |
Organisation | Beijing Synchotron Radiation Facility |
Country | China |
Sector | Academic/University |
PI Contribution | cd data collection and analyses |
Collaborator Contribution | beamtime made available |
Impact | publications |
Start Year | 2013 |
Title | cdtoolx |
Description | open access downloadable software for processing and analysis of CD data |
Type Of Technology | Software |
Year Produced | 2018 |
Impact | many UK and international users used for teaching and research purposes |
Title | this package of tools include many new analysis websites |
Description | multiple websites for different types of analyses of proteins based on CD spectroscopic data and its relationships to other biophysical methods the outputs were realised in all years of this grant so far (from 2017-2019) but this form only allows one year, so i have chosen 2019 |
Type Of Technology | Webtool/Application |
Year Produced | 2019 |
Open Source License? | Yes |
Impact | large numbers of publications by UK and other groups world wide use and cite this software and use it for teaching purposes |
Description | Engagement with International Elixer programme |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Study participants or study members |
Results and Impact | Elixer group on Intrinsically disordered proteins organised through £40,296 |
Year(s) Of Engagement Activity | 2019,2020 |
Description | Royal Society of Chemistry Awards Panel Member |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | RSC Panel reviewing nominations for Annual Awards |
Year(s) Of Engagement Activity | 2020,2021,2022 |
Description | Running training workshops for students, postdocs and industrial scientists on CD spectroscopy |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Teaching Lectures and Practicals in multi-day workshops to provide new skills training and ideas and information for researchers both nationally and internationally |
Year(s) Of Engagement Activity | Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018 |
Description | School visit (Tonbridge schools science day) |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Keynote speaker and poster judge at Tonbridge Area Schools Science day |
Year(s) Of Engagement Activity | 2019 |
Description | Talks at UK and international sites and meetings: Brazil Synchrotron Symposium, ), University of Vienna Austria (Chemistry Dept), Biochemical Society Training Course (Aston University, UK) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Talks about Tools and Resources developed in the course of this grant at Universities and International meetings, including the headline talk at the inauguration of the Brazil Synchrotron SRCD beamline (CEDRO) held for the international community of SRCD users and potential users, The Biochemical Society training course on Membrane Proteins at Aston University, the chemistry dept at the University of Vienna. |
Year(s) Of Engagement Activity | 2022 |
Description | Teaching at National and International Workshops for students and postdocs on the tools and resources we have developed |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Training workshops on CD spectroscopy in the UK (Leeds and Birmingham), at meetings in the US (NIH Biophysics Course), at the EBSA Biophysics Workshop in France, and the IUPAB Workshop in Cuba. |
Year(s) Of Engagement Activity | 2018,2019,2020 |
Description | Teaching workshops for students, faculty and industrial scientists |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | A series of workshops on methods of analysis for CD spectroscopy given at national and international meetings and workshops, usually 2-3 days, including hands-on computing practicals. for phd and masters students, postdocs, professors and other academics and industry |
Year(s) Of Engagement Activity | 2009,2010,2011,2012,2013,2014,2015,2016,2017,2018 |
Description | UCL-ISMB Prizewinners Symposium |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | Prize Winners Symposium (i was invited as i won the RSC Khorana Prize in 2020 |
Year(s) Of Engagement Activity | 2020 |
Description | annual talks for the public |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | UCL Science Centre Friday Evening Discourses and Birkbeck SET Talks for the Public talks on science for the public (5th, 6th form, and public) annually and lecture/tour at the Wellcome Collection talks no actual impacts realised to date |
Year(s) Of Engagement Activity | 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018,2019,2020,2021 |
Description | international advisory boad (germany) |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | international advisory board (Germany) |
Year(s) Of Engagement Activity | 2011,2012,2013,2014,2015,2016,2017,2018 |
Description | international advisory board (australia) |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | international advisory board for scientific centre of excellence (australia) |
Year(s) Of Engagement Activity | 2008,2009,2010,2011,2012,2013,2014,2015,2016,2017 |
Description | talks at national and international meetings |
Form Of Engagement Activity | Scientific meeting (conference/symposium etc.) |
Part Of Official Scheme? | No |
Type Of Presentation | paper presentation |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | in UK, USA, Australia, Austria, Belgium, Taiwan, Denmark, France, Germany, China, Brazil, Japan: talks at international meetings and workshops established new collaborations |
Year(s) Of Engagement Activity | Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014 |