ABOUT INTEGRATIVE STRUCTURAL BIOLOGY
A central driving force to initiate the theme “Integrative Structural Biology” (ISB) in 2017, was developments in the area of structural biology methods combined with new computational possibilities, and in particular the possibility to combine structural data from several methods through integrative approaches. With the rapid progress in for example the fields of macromolecular crystallography, cryo-EM, small angle scattering and the use of XFELs, the scientists did not always know the different possibilities and how to best combine data from complementary structural biology techniques.
The aim of the ISB theme was to promote work that enables the scientific community to use and combine a range of structural biology methods. To achieve this the plan was to organize a range of scientific meetings and workshops with the aim to:
Highlight recent developments and the complementarity of different techniques, in particular, important developments in the most challenging area.
Initiate discussions and work in areas that can contribute to the development of integrative structural biology.
Educate graduate students and postdocs in the practical aspects of an integrative structural biology approach as well as the latest structural biology techniques.
The theme was run between 2017-2022 (it was extended one year due to the COVID-19 pandemic) and has contributed to stronger and better communication between scientific areas that were previously more separated. During the years that ISB has been active, three larger symposia were organized. After two very successful ISB symposia in 2018 and 2019, the ISB core group decided to have the final ISB symposium in May of 2022. The final meeting, with approximately 100 participants, was truly successful. The three-day meeting was inspiring with the program having a mix of invited keynote speakers as well as many short talks creating a lot of interactions. In addition, a round table discussion centred around the future of structural biology was organized, which was very well received. The discussions were centred around how structural biology can be better intertwined with the clinics, how structural biology can contribute even more in the future and how communication can be improved.
Although the ISB theme has come to an end within LINXS, the theme has contributed to many important things for structural biology in Sweden and the Nordic countries. This is supported by the fact that SciLifeLab initiated an ISB platform in 2021 (https://www.scilifelab.se/news/infrastructure-update-the-integrated-structural-biology-platform-isb/) showing the importance of integrative research within the structural biology community in Sweden. Another initiative to strengthen ISB research in Lund was the start of the working group, Lund Integrative Structural Biology Centre Initiative (ISBC) in 2020. The working group aimed to investigate if there is an interest, in the Lund area, of a future integrative structural biology centre placed at Brunnshög, and to help catalysing the discussion and development of these ideas. A workshop was held in February 2021 with four invited speakers from integrative structural biology centres in Europe.
For this meeting, PIs who are directly working with structural biology in Lund were invited. After the meeting, the participants were asked to fill in a survey. One question was if the invited PIs thought that an ISB centre should be established in Lund, and 93% of the participants were positive towards the establishment of ISBC. As such a positive response was received, the working group decided to go further with the plans and submitted a letter to the University management. The letter was also received very well from the management and there are ongoing discussions on how this will be executed.
The membrane protein working group was formed towards the end of 2019 after a couple of brainstorming meetings with both local and international participants interested in the research area. The outcome of these meetings was the successful official formation of the working group, as well as identification of key topics that were aimed to be addressed, and suggestions for activities. During 2021, the group had two successful workshops, the first one focused on protein expression and sample quality control, and the second focused on sample preparation for structural biology and structure determination by different methods such as X-ray crystallography, neutron crystallography and single-particle cryo-EM. Both workshops were held online with roughly 100 participants from all over the world.
The amyloid working group organized several workshops for instance two with the focus “User-friendly analysis of spectroscopy data with Quasar - multivariate statistics and machine learning”. These activities were based on a collaboration between the French SOLEIL light source, MAXIV and the Faculty of Medicine. A meeting entitled “Heart and Mind”, focusing on cardiomyopathy and neuropathy in relation to amyloidogenesis was held in 2021. As a follow-up activity, the working group produced a conference report published in the Journal of Translational Medicine: “Recommendations for addressing the translational gap between experimental and clinical research on amyloid diseases This paper is a report of recommendations for addressing translational challenges in amyloid disease research.” prepared by the group members. The key suggestions include improving cross-cultural communication between basic science and clinical research, increasing the influence of scientific societies and journals (vis-à-vis funding agencies and pharmaceutical companies), improving the dissemination of negative results, and strengthening the ethos of science.
The time-resolved structural biology working group has during its active years concentrated on the organization of several Time-Resolved Structural Biology workshops. While the first workshop had a broad programme that highlighted what can be done with different methods, the second workshop focused more on crystallography including experiment design, results and facilities, and also more talks and discussions on data interpretation, how to avoid pitfalls, and on what developments that are important for the field. In terms of techniques the programme covered NMR, SAXS, CryoEM, crystallography, and computational methods. In addition to a longer discussion session for each half day, the coffee breaks, lunches, poster session and the workshop dinner gave ample of time for interaction between the workshop participants. This contributed to the very positive feedback that was received.
CORE GROUP
GUEST RESEARCHERS
WORKING GROUPS FOR INTEGRATIVE STRUCTURAL BIOLOGY
ISB WorkING Group 1
Biocompute AND Artificial intelligence & Machine learning
The Biocompute Working Group seeked to address several fundamental issues such as:
Novel and refined program packages are needed for new MX/neutron technologies (XFEL, neutron data from spallation sources, and much more)
Integration of state-of-the-art Applied Maths in existing software
Appropriate research education to better understand processes that links data to results.
A need to learn how to better use HPC more effectively than we do today.
A need to see, learn and integrate the potential for machine learning & AI-techniques in our analysis.
They focused their work on project oriented SB-users with complex scientific questions (multi-modular, dynamic, size and more), experimental infrastructure personnel/researchers, HPC personnel/researchers, user platforms and applied mathematicians and programmers.
ISB WORKING GROUP 2
TIME-resolved structural biology - new possibilities in a time of new facilities
Time-resolved structural biology aimed at determining structural intermediates in order to understand the function of e.g. proteins. Work in the area of time-resolved crystallography, first at synchrotron sources and more recently also at X-ray Free Electron Lasers (XFELs) has shown that it is possible to study structural events down to very short time scales. One important development follows the fact that very small crystals can now be used. It makes it possible to trigger events with diffusion in much shorter time scales and to study irreversible reactions common in biology, which makes the time-resolved techniques potentially much more generally applicable.
Time-resolved crystallography must be complemented with other techniques, e.g. different spectroscopic techniques to verify that what happens in the crystal is the biologically relevant reaction. In a broader sense, other techniques such as XAFS, SAXS, neutron spectroscopy, NMR and molecular dynamics are important to give a more complete picture.
There are however challenges in time-resolved crystallography, for example: Finding the best way to trigger a reaction is an issue that has to be solved for each individual case, though there are general strategies that can be developed. Data sets are often assembled from multiple crystals, which are often heterogenous. Typically, there is only a fraction of the molecules in the desired state making it difficult to interpret the data. Collecting data while a reaction is taking place can lead to disorder in the crystal and loss of resolution.
ISB WORKING GROUP 3
AMYLOID: AN INTEGRATIVE APPROACH
Amyloid and amyloid type systems are implicated in a wide range of diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, type 2 diabetes mellitus, and a variety of transmissible spongiform encephalopathies. While extensive structural studies have been carried out on many amyloid forms, there remain major questions about the amyloid deposits associated with these pathologies and about the way in which they assemble. Generalised structural information derives from fibre diffraction, NMR (notably ssNMR), some single crystal information from short peptides, and more recently cryo-EM. Despite the major biomedical importance of this area, major challenges exist in all of these approaches, and the linkage between them is often poor or absent.
The working group aimed to initiate a discussion forum amongst researchers working on amyloid using a wide range of different approaches ranging from molecular level approaches to imaging & clinical work. The topic therefore relates primarily to the LINXS mission within the Integrative Structural Biology theme, but may have natural connectivities to the other current themes. The main beneficiaries will be researchers active in this important area of human health, as well as any evolving technologies or synergies that arise. It is planned that this group will probe important issues that problematic to the field, and also stimulate a wider holistic discussion.
ISB WORKING GROUP 4
MEMBRANE PROTEINS - Structural Resolution and Homology Modeling
The Membrane Proteins Working Group was organized to bring a collective focus to scientific questions and issues pertaining to the structural biology of a wide variety of membrane proteins. With the local emergence of the Scientific Infrastructure developments, MAX-IV and ESS, it was very timely to organize greater efforts relevant to increasing knowledge and efficiency of research on the great diversity of membrane proteins. There has long been a challenge in structural determination of membrane proteins, relative to non-membrane proteins, due to the intricate associate between the proteins and the cellular lipid bilayer membrane, though much progress has been made in this area in recent decades. The working group aimed to leverage such progress, to streamline information flow of current state of the art knowledge for greater accessibility by the structural biology community and non-structural biology end-users who have research interests in such questions on the structure of membrane proteins.
ISB WORKING GROUP 5
Lund Integrative Structural Biology Centre Initiative
Working group to investigate if there is an interest, in the Lund area, of a future integrative structural biology centre placed at Brunnshög, and to help catalysing the discussion and development of these ideas.
Today the structural biology community in Lund is strong but spread out at different faculties and different buildings within the Lund campus. This has both advantages and disadvantages. However, with the construction of both MAX IV and ESS and the future Science Village Scandinavia at Brunnshög the working group aims to investigate if there is an interest in the Lund area of the creation of a structural biology centre placed at Brunnshög. By organising workshops, different aspects of a Brunnshög centre can be better understood which will help making the ideas concrete. It can also strengthen collaborations, both in the Lund area but also nationally and internationally, which can be important for how structural biology benefits from MAX IV and ESS.
ISB Core Group Leader, WG 5–Lund Integrative Structural Biology Centre Initiative leader, and WG 4–Membrane Proteins member, LINXS Fellow
Karin Lindkvist is an expert in structural biology in particular applying X-ray crystallography. Her research encompasses both structural studies of integral membrane proteins and soluble proteins, in particular proteins important in human metabolism such as glucose transporters and glycerol channels. Lindkvist has a strong scientific network in the field of membrane protein structural biology.