Department of Structure and Dynamics of Nucleic Acids

Our main research aim is to provide unique insights into the role of molecular interactions in structure, dynamics, function and evolution of nucleic acids (RNA, DNA, and their complexes with other molecules), as well as chemical processes involved in origin of life. Our research is highly interdisciplinary and we wish to bring modern physical-chemistry insights into structural and molecular biology, biochemistry and bioinformatics. We use a wide spectrum of state-of-the-art computational techniques, including explicit solvent molecular dynamics simulations, advanced ab initio quantum-chemical calculations and modern bioinformatics. For the origin of life research, we also utilize experimental methods. Due to interdisciplinary nature of our research, the background of our team is very diverse, including biologists, biophysicists, biochemists and physical chemists. As such, our research has impact also in some other areas of chemistry, such as physical, supramolecular and bioinorganic chemistry.

Summary: our scientific goal is understanding of the most basic principles of structural dynamics, function and evolution of DNA and RNA.

Main methods of our research:

1. Classical explicit solvent molecular dynamics (MD) simulations – allows us to study large nucleic acids systems containing hundreds of nucleotides, as well as their complexes with proteins. The currently available simulations can be extended to dozens to hundreds of microseconds depeding on the size of the studied system. With this technique, nucleic acids are modeled at the atomistic level of description using classical potential functions known also as empirical force fields. Approximations inherent to the force fields represent the main limitation of this approach and our team is heavily involved in force field testing and development.

2. Enhanced sampling MD simulations – great disadvantage of classical MD is that despite constant hardware advances, their available timescale is still insufficient to capture many biologically relevant processes. One way to overcome this problem are the enhanced sampling simulations. These most often involve a selection of additional parameters (for example, the distance between protein and nucleic acid) whose conformational searching is accelerated by modifying the basic force field. The limitation of enhanced sampling is that it sometimes oversimplifies the studied processes. Enhanced sampling also tends to exaggerate existing problems within the force field although this can also be useful when testing new versions of the force field.

3. Ab initio quantum chemical (QM) technique is state of the art physical-chemistry methodology that provides accurate and physically complete description of small model systems. The technique reveals direct structure – energy relations that cannot be obtained by any other technique. Such calculations have indispensable role in reference evaluation of nature and magnitude of all kinds of molecular energy contributions that shape up nucleic acids, such as base stacking, base pairing, backbone conformational preferences, etc. QM calculations allow to study chemical reactions at a level of electronic structure changes.

4. The origin of life – our laboratory is well equipped to perform basic chemical and biochemical experiments. State-of-the-art analytical techniques, like polyacrylamide gel electrophoresis, MALDI-ToF mass spectrometry, HPLC-MS are available in cooperating laboratories at the IBP, CEITEC MU or abroad (LMU-Munich). We also intensely collaborate with Tescan Brno on material imaging using electron microscopy.

Other utilized methods: Hybrid quantum-classical (QM/MM) methods, Structural bioinformatics

Our modern computational methods are often combined with many experimental techniques (NMR, X-Ray, high-energy lasers, biochemical techniques) mostly via numerous collaborations. We collaborate with ~30 foreign and Czech laboratories. We publish about 15 papers annually and belong to the most cited Czech research groups. See the full list of papers on this web page. We have excellent in-house computer facilities, which are regularly upgraded.

We currently work in several mutually interrelated research areas

1. RNA structural dynamics, folding and catalysis.

2. Protein-RNA complexes.

3. DNA, with focus on G-quadruplexes.

4. Diverse types of quantum-chemical studies on nucleic acids systems.

5. Origin of life (prebiotic chemistry), i.e., creation of the simplest chemical life on our planet (or anywhere else in the Universe), with a specific attention paid to the formamide pathway to template-free synthesis of the first RNA molecules. This specific project includes also in house experimental research.

Besides studies of specific systems, we are also involved extensively in method testing/development, mainly in the field of parametrization of molecular mechanical force fields for DNA and RNA.