The mechanism that proteins employ to fold and unfold (folding and unfolding) is a key to treatment of many severe diseases, including cancer. The scientists know that the proper protein structure is formed on a step-by-step basis. First, stable secondary structures, such as strands and helices, are formed. They then fold in a proper knot. For a long protein molecule to get tied in a knot, there should be a coordinated collective behavior of a molecule as a whole, as if someone knowingly ties a molecule in a knot. Such behavior makes a protein a very important subject of research not only for biologists, but also for physicists. According to the classical field theory, movement of each single atom can be interpreted as a part of the general degree of freedom (soliton) with a certain number of generalized coordinates, Aleksandr Molochkov, Head of the Pacific Quantum Center at FEFU, says. The example of a soliton is a tsunami wave with its destructive power. Is the behavior of the protein in any way similar to that of the tsunami? And how will this fact allow the academic community to find medicines against neurodegenerative and cancer diseases? Aleksandr Molochkov is here to explain.

Aleksandr Molochkov is a Professor, Dr. Sc. in Physics and Mathematics, Head of the Pacific Quantum Center at the Far Eastern Federal University.

In your recent research, you examined an interesting process, that is protein folding. What are the main objectives of your research and what conclusions did you reach?

— The protein studies are famously very important, especially when it comes to medicine. In 2020, for example, the academic community paid a lot of attention to this matter: what a new virus is, which cell proteins it bonds to, etc. I mean, the topic is top-of-the-agenda like never before.

In general, the modern medicine is focused on research of different proteins and, specifically, receptor proteins, which are responsible for effects of any medications. Naturally, there is a large community being formed around this topic pursuing research in different areas.

Our team is quite unusual when it comes to protein research, because it consists solely of theoretical physicists. Although we cooperate with molecular biologists and scientists who specialize in molecular biophysics, in general, the research is the domain of theorists who typically study the particle physics.

How did this happen? We found out that our methods can be used to study proteins. And that was the point of our research — to find new tools to study the protein dynamics. Why is it important?

In December 2020, the DeepMind algorithm predicted the protein structure by the amino acid sequence. The machine learning technologies moved to a new level, as they can predict the structure. But predicting the protein dynamics is challenging even for the computer.

To understand how the protein changes in the medium and interaction with other molecules, it is necessary to determine not only its structure (which can be measured by the X-ray crystallography for that matter), but also to learn to predict how the protein behaves in different conditions. The modern methods are unfortunately helpless, as the protein is a very big, complex molecule, consisting of a hundred and sometimes a thousand amino acids. But every amino acid is composed of many atoms. With contemporary, fairly rapid development of computing capacities, we, by some estimates, will need a few thousand years to build a computer capable of calculating the protein dynamics the traditional way. This is precisely why we decided to use other methods, which do not require tracking the movement of each single molecule, but consider the protein as a whole, a common medium subject to integral laws.

Let us say, models, which describe the behavior of water as some collective medium, are used to predict the tsunami wave dynamics. Understandably, it’s no use describing the tsunami by movement of separate water molecules. Such methods are also used in protein research. For example, our colleagues of the University of Tours in France developed a model, predicting the protein structure, using this method. We improved the model and began to study the dynamics.

Myoglobin model

Myoglobin model

Source: Wikipedia / AzaToth

Myoglobin became the first test subject. My colleagues and I predicted how its structure changes and even created the respective animation, showing how it folds and unfolds.

We then decided to reproduce what no one could do ever before — the protein ability to create topologically nontrivial structures. The most obvious example is a knot. Every child knows that you cannot tie a string in a knot by simple and random movements. You need to make certain, well-considered moves to tie a butterfly knot, the simplest of the knots. As a matter of fact, we chose a protein, the structure of which reminds of a butterfly knot.

In this case, no molecular dynamics is working. Many scientists tried to reproduce this process, but the percentage of configuration that folds in the necessary knot is next to none. But in nature, this protein produces some very strong knots. As I said, random wandering doesn’t give you anything, you need to have some coordinated movement.

Our model successfully predicted not only folding in a butterfly knot, but also produced different interesting stages of this process. For example, the protein at some point in time is very much compressed and reduces molecular radii to get tied in this knot. At some point, it forms intermediate knots, much more complex than the final ones. We now expect the necessary experiments to be held, which will either confirm or confute our models.

Speaking of cooperation with molecular biologists, we found an objective that we shared with our colleagues of Cornell University (USA), which back in the day was headed by Harold Scheraga, a father and one of the founders of the modern molecular biology, who greatly contributed to the vision of the protein folding and who unfortunately passed away in 2020.

He built a strong team of scientists who were intrigued by our approach. It appeared that the soliton-based protein model is great to explain the folding or unfolding of molecular chains of protein molecules.

— Does your research have any applications?

— These processes are explored from the viewpoint of fundamental tasks for the time being. The underlying idea of this approach is that the protein behavior is fully determined by the symmetry properties — the basic concept of the modern theoretical physics. You must have heard about the Higgs boson and years of searching for this particle. This is one of the examples when scientists were not just looking for a new particle as such, but trying to confirm the fundamental concept of nature, stating that the symmetry defines the laws of nature.

In our case, we rely on the fact that the local protein symmetry, its topology, in other words, the form of the molecule itself defines the protein behavior. The symmetry breaking and Higgs mechanism are also used to explain the emergence of ordered structures, such as helices and sheets.

Speaking of applications, the future development of a tool that will be able to predict the protein form and its dynamics will become indispensable for the modern pharmacology and computer screening. It will considerably reduce computing capacities required to search for a necessary molecule that will bond to specific protein receptors, and understand how the protein changes in the interaction. A practical way out is possible, but this matter is more in the realm of biologists and pharmacologists who are still having a hard time adopting new methods.

In the meantime, we are already beginning to interact with certain teams specializing in receptor proteins. For example, there is a strong team headed by Valentin Gordely at the Moscow Institute of Physics and Technology (MIPT). They are working with receptor proteins. And we are already discussing joint projects.

— The Pacific Quantum Center was established very recently. Can you tell us why it was established and what areas of research it will further develop?

— Let me speak in a roundabout way. As a graduate of the Far Eastern State University myself, I went to Dubna where I worked for some time solely in the field of nuclear and high energy physics. But I still had nostalgia. I wanted to gather a strong team of theorists. I understood that it was hard to get a team of experimenters, as experiments in high energy physics require high investments, which was impossible to attract in the 2000s. But the dream lived on. It was also fueled by the fact that very many FEFU graduates work at leading Russian and foreign centers, but we have nothing new established in the Far East and the science does not advance. So, after my next postdoc, I returned to Vladivostok and tried to assemble a team of associates. I understood fairly soon that it was no use fixing on something very narrow, as one of the big advantages of theoretical physics is the ability to use general ideas to explore completely different things relating to condensed matter physics, materials science, biology, etc.

As a result, a diverse group began to form at the Center for Chiral Biophotonics. Some of my colleagues were researching purely quantum chromodynamics, some others — proteins and yet others — graphene. Gradually, through different interesting workshops, schools, etc., we found common ground for joint research.

Later, we also came up with a common notion of symmetry. As a result, we benefited from the advantage of theorists who can solve most diverse problems. We won a pretty large grant under the Science national project, which allowed us to establish the Pacific Quantum Center, an institute with the single scientific agenda, a place where all components have their own logic and researchers do not just share the knowledge, but work together as part of the joint projects. The Center will hopefully bring some interesting results.

— What equipment do you use to conduct research? Is it just powerful computers or is there any instrumentation?

—Let me tell you a joke and many theorists will understand what I mean.

The ultimate instrument (and I had to prove it to university accountants back in the day) is a coffee machine. Because what is theoretical physics? This is a conversion of coffee into formulas.

Yet the ultimate instrument is of course a supercomputer. We have a quite powerful supercomputer, which we currently improve. But a strong team of specialists who can program on graphic map displays is also important.

This, of course, is an extra problem for me as a leader, as professionals are always solicited by others. Today, good specialists are highly valued everywhere.

As for the instrumentation, we are actively working on it. For the research center to remain stable rather than transform into a virtual entity, we came up with an idea to build a basic installation. In this matter, we get help from colleagues in Novosibirsk, Sweden who are currently building a MAX V unit. As we are focused on the source of photons, we plan to build a compact linear accelerator, which will enable us to test our theoretical ideas right in the lab. But, for now, this is a matter for the distant future. Because many different factors, financial, political, and others, must work out in order to build such an installation.

—How many employees does your center have?

— We have 22 employees working on the project as part of the state assignment. But we take part in the project funded by the RFBR grant and related to the NICA installation. So, overall, we have around thirty people. And I say “around,” as I cannot give you the exact number. This could be inexcusable for a leader, but we have temporary employees and those who are not officially employed at the center, yet they take an active part in its work.

60% of our staff is young professionals, students, postgraduates, many of them, fortunately. We also partnered with prominent, very famous scholars. For example, Atsushi Nakamura, Professor at Osaka University (Japan), works here, in Vladivostok. He gives lectures and helps postdoctoral researchers. And, curiously enough for his respectable age, he offered a new research topic, which we began to elaborate — the use of machine learning to study the quark-gluon plasma and proteins. A very creative person.

I cannot but mention Valentin Zakharov, one of the scientists who greatly contributed to the modern quantum chromodynamics; Maxim Chernodub, Professor at the University of Tours in France, who at some point headed the Top100 of the most cited Russian researchers. He is very active and sometimes, I feel that he works with my postgraduate students more than I despite the fact that he lives in France.

We have a large staff, but it is not all concentrated in Vladivostok. Young researchers work in Russia, while professors chiefly visit us several times a year or give lectures over Zoom or Skype. A year ago, it seemed unusual and maybe not very real, but it became a reality for all of us due to the pandemic. As a result, we were ready for it, although we didn’t know it might actually happen. For our center, nothing has changed really, as we continued to work, using the same technologies.

— What are you working on today and where does the Center go?

— Today, we are working on three very important projects. One is carried out in partnership with our colleagues from Dubna for the NICA unit — the use of machine learning to make predictions in the area of physics where we cannot calculate figures directly, even using our supercomputer. For example, phenomena in the dense quark-gluon plasma from exposure to the magnetic field. So, on the one hand, this is a very fundamental thing, but, on the other hand, it offers lots of answers to questions how our universe appeared in the first place, what laws govern the matter.

The second area of research is proteins and the so-called amyloid proteins. What makes them so special is that they don’t have a well-defined structure. It changes a lot depending on the medium conditions and other factors. One of the most important uses is treatment of neurodegenerative and other severe diseases, such as Alzheimer’s disease, type II diabetes, and others.

The third area of research is dedicated to the abnormal transport in quantum materials. After the discovery of graphene, there appeared many other quantum materials, such as Weyl and Dirac semimetals. The mankind expects much of these materials, especially from the viewpoint of practical uses. One of the discoveries, which, I think, is essential for the modern science, comes from the discovery of negative magnetoresistance as a result of the chiral magnetic effect predicted by the famous scientist Dmitry Kharzeyev. This effect will undoubtedly offer many applications in magnetically controlled electronics, warm superconductivity and quantum computers.

— Do you think you made your dream come true to gather the most talented team in the Far East?

— My colleagues think I did. I am more pessimistic for that matter, as I did gather talented specialists alright, but this is only the first step. I need to make personal efforts, finding talented school students at the skills competitions and master classes among them and then watching and assisting them from the first year of university study to the last one. But I really would like there to be a system. Therefore, the main challenge today is to arrange a good vertical rotation of young professionals so that new students could come and those who already work with us could develop, improve their skills as postdoctoral students and come back. Then, and only then I will be confident that this truly is a real, living structure rather than a temporary phenomenon.

Interview sponsored by the Ministry of Science and Higher Education and the Russian Academy of Sciences.

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