“The gain in insights for structural biology has continued for five decades”

Prof. Dr. Udo Heinemann works at the Max Delbrück Center for Molecular Medicine, where he has been researching in structural biology for 40 years. From 2008 to 2012, he was a member of the Advisory Board for the Protein Data Bank in Europe. In an interview, he speaks of the value added by the Protein Data Bank for research today, and why it is important that there are specialised beamlines for structural biology analysis in Berlin.

This year, the 50th anniversary of the Protein Data Bank is being celebrated internationally. It contains more than 170,000 protein structures at present. What value does the Data Bank have for research today?

The Protein Data Bank (PDB) demonstrates the enormous worldwide activity that is going on in structural biology. While in the initial years it grew slowly, over the last decade it has been receiving floods of new structures. The added value for research is huge. There are two user groups: those who enter structures into the data bank, and those who do further research on the published structures. My team and I have fed more than 250 structures into it so far. Archiving media have changed many times in the past 50 years, and we wouldn’t be able to read some of the early data today. The PDB takes the burden of sustainable data archiving off the researcher’s shoulders. The structures are preserved for posterity at three international locations, where they could even survive a nuclear event.

What kinds of structures are recorded in the PDB?

All three-dimensional molecular structures generated from experiments can and should be recorded in the PDB – no matter whether they have been identified by protein crystallography, magnetic resonance spectroscopy, or cryo-electron microscopy or tomography. The majority of them are crystal structures determined by X-ray diffraction. Before structures are put into the Protein Data Bank, they go through a validation process. This is like stamping them with a seal of quality.

So, scientific quality assurance is an important function of the Protein Data Bank?

Absolutely! In the past 50 years, the Protein Data Bank has helped immensely in setting new standards. That goes not only for the structures themselves, but also for the experimental data behind them. Such quality standards have established themselves through intensive discussion within the scientific community. This validation process is very important because it means researchers can trust in the fact that the PDB contains only tested, quality-assured structures.  

The Protein Data Bank contains structures from 50 years ago. What use is there for today’s researchers being able to access structures that are 50 or even 30 years old?

Even old data are very important. In addition to molecular structures, the PDB also contains the experimental data from which those structures were determined. These days, you can reanalyse old data using new methods and arrive at even better protein models. Indeed, there are plenty of old structures that seemed unspectacular at first, but which later gave rise to a lot of research and great publications.

Could you give an example?

Some years ago, in experiments done partly at the BESSY II MX beamlines, we discovered so-called cold shock proteins, which perform important biological functions. These proteins are still very exciting and, to this day, we are discovering new functional relationships with them. Unfortunately, one cannot always predict while performing experiments which protein class will turn out to have great potential in the next ten years, for example in computer-aided modelling of new protein structures. This is where methods like artificial intelligence also come into play.

You hint at the importance of simulations and AI in gaining new insights. Will this mean fewer experiments will be needed in the future?

Not at all! Even if AI has advanced in great strides over the past five years, experiments are essential. We need experiments for making truly new discoveries. One exciting example, which we recently discovered at BESSY II, is proteins with so-called UBX domains. These bind to certain ATPases, specifically p97 proteins that control mechanical activities in cells. For a long time, it wasn’t clear how these UBX domains bind to p97 and transport the ATPase to target sites in the cells. And then, a few years ago, we discovered a UBX domain that behaves completely unexpectedly. We had discovered something that nobody had predicted. You cannot make such discoveries with modelling alone.

The experiments in question ran at the MX beamlines of BESSY II, where structural biology studies have been going on since 2001. How did that get started?

In the late 1990s, an initiative was launched, which I led as the coordinator. One of the objectives was to build beamlines for structural biology experiments at BESSY II. At the time, the Federal Ministry of Research was providing a lot of money for flagship projects in the field of molecular medicine. From this pool, we received around 30 million deutsche mark. With a share of those funds, we were able to install the first MX beamlines and the experimental hutch, as well as the wavelength shifter for producing the hard X-ray beam. At the initiative of the MX Team at BESSY II, these beamlines have been comprehensively modernised in recent years. Looking back, I can say that our launch initiative in the 1990s has led to something truly wonderful.

What is the importance of the MX beamlines today for the scientific community?

The MX beamlines are very successful and benefit a large scientific community, which is also highly international. There have been countless papers from experiments on the BESSY II beamlines published in high-ranking journals. Everyone involved can be proud of that. While the predominantly soft X-ray light from BESSY II is not optimal for our experiments, the MX stations are internationally competitive because they are beautifully managed, and everything that is offered for the experiments is top class. That is how the MX Team has gained the loyalty of the large user community. For the Berlin universities, too, the experimental facilities at BESSY II are an important advertisement for acquiring talented researchers in structural biology.

Many new insights have been gained in structural biology in recent years. What social value is added by this research?

In all my time as a structural biologist, so for a good 40 years, insights from this field have never been missing from the front pages of top journals like Science or Nature. Science tends to follow certain fashions and waves, but structural biology has been highly popular for 50 years and will continue to be so. We mostly do basic research, which has a very high value even before it comes to the applications. And then, protein structural analysis plays a very important role in drug development. Almost all new developments of active compounds nowadays are based on structural analyses. They are an integral part of a large pharmacological toolbox for developing new drugs. BESSY II has a leading role in this as well. We have a method for rapidly testing different active ingredients, called fragment screening. The most recent example is the search for a drug against Covid-19. Researchers have conducted excellent protein analyses on the SARS-CoV-2 virus – including right here at BESSY II.