Bioinformatics Resources for Circular Dichroism Spectroscopy and Structural Biology: Operation, Enhancement, Curation, and New Developments

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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.

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 biomacromolecules, 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 the 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.