The collaborative computational project for NMR (CCPN): supporting biological NMR for the biosciences, medicine and industry.

Structural biology concerns the study of the three-dimensional structure of biological macromolecules and their interactions. Biomolecular Nuclear Magnetic Resonance (NMR) spectroscopy is one of three core techniques in structural biology, and highly complementary to the other two, i.e. X-ray crystallography and Cryo EM.
Extracting information from NMR data has traditionally been complex and non-intuitive. Many smart and innovative tools have been developed, which unfortunately often have been disconnected and not well integrated and sometimes hard to use. For nearly two decades, the Collaborative Computational Project for NMR (CCPN) has been central in providing a connecting interface between the NMR data and many of these tools. CCPN also actively promotes the sharing and exchange of knowledge and best practices. CCPN also actively engages with the UK and international research communities in all matters relating to research funding and policies.
The CCPN aims to continue its immense value to the scientific community over the next 5 years by pursuing the following specific objectives:

1. Development of software relevant for NMR
CCPN will improve, maintain and expand its programmes, to provide for new functionalities, improved handling, and better speeds. Through fortnightly updates and regular new releases, we will ensure the proper functioning of the software across multiple platforms. We will continuously work on interoperability of our software with other NMR programmes and implement relevant tools for reporting and research data management.

2. NMR in support of Biological Sciences
We will facilitate and implement the latest computational tools and developments for NMR data analysis, automation, structure generation and validation.

3. NMR in support of Medicine
NMR metabolomics is a thriving field that generates crucial knowledge on metabolic pathways from cells to organisms, including humans. We have designed AnalysisMetabolomics to leverage its power and we will focus on tools for non-expert users, streamlined annotation, assignment, metadata and deposition in public repositories.

4. NMR in support of Industry
In collaboration with industrial and academic partners, we will test and enhance applications that are useful to industry. Examples are AnalysisScreen, small-molecule (NMR-assisted) docking procedures to optimise workflows and efficiency and ChemBuild to assist with fragment-based drug discovery.

5. Outreach and training
Through its active outreach programme, engaging with all stakeholders including national and major international NMR facilities, CCPN will promote the continuous exchange of knowledge, provide training and support the adoption of best practices in NMR. There is a growing body of "how to" videos available on the website. CCPN will actively continue to promote and develop community data standards (NEF), and will take a leading role in discussions on research funding and policies.
CCPN will continue its crucial role as intermediary between the UK and international NMR community, by fostering contacts with (inter-)national NMR facilities, other CCPs, the international wwPDB and NEF efforts.
To strengthen the UK NMR community, we will continue the successful series of UK CCPN conferences and teaching programs, our comprehensive help and support for CCPN users, participate in international efforts in knowledge sharing and exchange of best practices, and engage in training and teaching through workshops, papers and (video) tutorials.

In short, CCPN will continue to make a crucial difference to the biological NMR community in different fields such as Medicine and Industry as well as its traditional base of the biological sciences by acting as a focal point for technology development, collaboration and sharing best practices. Ultimately, researchers who are empowered with the best tools have more time to make new discoveries.

CCPN has developed a graphics-based, adaptable and easy extendable NMR data analysis software platform for users which covers all aspects of biological NMR, including small molecule applications in NMR-based metabolomics and NMR-based screening. Our efforts are focused on easy spectrum visualisation and interpretation, smart tools for data analysis, NMR-based structure calculation and validation.

This MRC partnership proposal aims to continue, enhance and advance the application of NMR in the biomolecular sciences through the development of novel tools, technologies and methodologies, knowledge sharing and exchange, as well as training and support with a particular focus on early career researchers. It builds on 20 very successful years and CCPNs undisputed crucial and greatly valued role in the biological NMR community. CCPN aims to foster collaborations and to represent the community in all relevant matters related to research funding and development of (research) policies. CCPN achieves its goals by working with all stakeholders.

Specifically, the efforts of CCPN and its partners during the next 5 years will be directed to the following areas: 1. Development of software relevant for NMR 2. NMR in support of Biological Sciences 3. NMR in support of Medicine 4. NMR in support of Industry and 5. Outreach and training.
With the current proposal we establish a long-term vision and extended approach in nurturing the collaborations with crucial current and new partners, extending the scope of the project and confronting numerous interesting, yet challenging future issues. The latter include automation and smart AI-inspired tools, the relationship between NMR, dynamics and molecular modelling approaches, data exchange, and RDM.

The efforts of CCPN and its partners will be crucial to support the NMR biomolecular scientists in tackling many of the 21st century scientific challenges in our understanding of disease and the development of personalised medicine.

The CCPN project is a long-standing, highly-regarded, advanced technological software development and community-building project. Its continued efforts are crucial as evidenced by the very widespread support across the UK and internationally (see letters). To date, the version-3 CcpNmr Analysis software suite presents the only modern, fully maintained platform that is optimised for all aspects of biomolecular NMR data analysis. CCPN's efforts in the development of international standards for data deposition and remediation and its role in shaping discussions on research funding and policies, are of crucial importance to the biomolecular NMR community. Thus, CCPN serves as an example of the acknowledged imperative for the UK to be a leader in the global knowledge economy.

CCPN's impact extends to several areas:
1. Supporting academic research excellence. The CCPN software package is essential for the research of a large number of UK and worldwide biomedical NMR scientists, including many MRC-funded PIs. Continuing support, improvement and expansion of the software with the latest state-of-the-art tools is essential, as these drive their biomedical NMR-based research programs and stimulate developments in data-centred science and -omics type research.
2. Support for industrial innovation and research. CcpNmr AnalysisScreen and AnalysisMetabolomics are dedicated open-source, readily customisable software platforms for fragment-based drug discovery by NMR and NMR-metabolomics, respectively. Thus, CCPN supports industrial innovation, in particular for small- and medium-sized companies that alone cannot afford their own development. Our industrial partners and the continuing industrial support of CCPN underscores this notion.
3. Providing a scientifically trained workforce. A well-educated and technologically skilled workforce is crucial for societal development. CCPN provides direct training for graduate students and post-docs who will form part of the UK technological workforce. By attending our conferences and workshops and using our software as a development platform, they are trained in scientific thinking, problem solving and scientific programming. These skills are widely applicable and useful well beyond the specific problems where they were first applied.
4. Driving technological developments that benefit the UK population through improved healthcare. NMR has emerged as a crucial tool in the quest for personalised medicine approaches. Not only does NMR contribute to our understanding of the structure and interactions of biomolecules in a variety of states (folded, aggregated, unfolded), NMR is widely used in the drug discovery process. Metabolomics is another technological development of great potential benefit to the general public. Accurate, detailed and timely detection of disease is nearly always beneficial for effective treatment and improves the chances of recovery. NMR has emerged as an excellent tool for the analysis of body fluids and for the attempts to elucidate relevant biomarkers. Specific metabolite patterns are starting to be recognised and correlated with specific disease states. Thus, NMR provides great potential as a diagnostic tool that will benefit society at large, as evidenced by the CCPN partners directly engaging with a clinical setting.
5. Education of the general public. Current secondary school pupils constitute the future generation of potential scientists. The NMR technique is part of the GCE A-level chemistry curriculum. The self-contained nature of the CCPN software tools and their dedicated provisions for 1D data, provide for an excellent way to familiarise pupils with the curriculum objectives. By providing real NMR data together with suitable tools, tutorial videos and hands-on approaches during science outreach days, the students' imagination is sparked.