J1-500033 Multiscale modeling of protein conformational dynamics
Project summary:
Computer simulations are becomming an inevitable tool for describing the dynamics and functions of biological macromolecules. We aim to provide new methodological solution for investigating principles of ion signaling and molecular transport in membrane proteins in selected protein systems. In particular, our goal is to provide computational tools for understanding of how observable macromolecular processes, carried out over a wide range of temporal scales, arise from molecular scale events which requires a combined use of different simulation and theoretical approaches as well as careful experimental validation. We will develop new simulation strategies to characterize thermodynamics and kinetics of biological processes involving conformational changes of proteins on the ms-ms time scale. Here we use two approaches, i) generalized Langevin equation (GLE) formalism and ii) metadynamics applied to various generalized coordinates / collective variables, which we derive from atomistic MD simulations in the known equilibrium conformational states using principal component analysis (PCA). In order to identify pathways along which energy transport takes place in proteins we analyze the coupling of the internal vibrational modes given as PCA modes and corresponding energy diffusion between them.
Our tools will be applied App1) to study of dynamical switching between conformations of CaM, stimulated by different calcium load, electromagnetic pulses as well as by binding of target peptides and App2) to obtain insights in principles of water transport in sodium-glucose cotransporters (SGLT), The former system will be used for validation of the simulation results obtained by the novel approach with a direct experimental data from the pump-probe experiments.
Research team
- Franci Merzel sicris 13627
- Petra Papež sicris 52000
- Matej Praprotnik sicris 19037
- Neli Sedej sicris 54913
- Barbara Zupančič sicris 28608
Participating organizations:
Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
- Karoly Liliom
- Gusztav Schay
- Erika Balog
Bibliographic references
Original scientific articles:
Gašper Šolinc, Marija Srnko, Franci Merzel, Ana Crnković, Mirijam Kozorog, Marjetka Podobnik & Gregor Anderluh, Cryo-EM structures of a protein pore reveal a cluster of cholesterol molecules and diverse roles of membrane lipids, Nat Commun 16, 2972 (2025). doi.org/10.1038/s41467-025-58334-z
Maša Lah, Nikolaos Ntarakas, Tilen Potisk, Petra Papež, Matej Praprotnik. Open-boundary molecular dynamics of ultraso und using supramolecular water models. Journal of chemical physics. [Online ed.]. 14 Jan. 2025, vol. 162, iss. 2, [article no.] 024103, str. 1-10, ilustr. ISSN 1089-7690. https://pubs.aip.org/aip/jcp/article/162/2/024103/3329569/Open-boundary-molecular-dynamics-of-ultrasound.
Presentations at conferences:
Karoly Liliom, Gusztav Schay, Gergely Burkódi, J Michael Klopf, Laszlo Smeller, Franci Merzel, Miklós Kellermayer, Erika Balog, Structural fluctuations of human calmodulin at low calcium saturations, Biophysical Journal, 543a-544a February 13, (2025) DOI: 10.1016/j.bpj.2024.11.2838, BPS2025 Los Angeles, Feb 15-19, 2025.
Neli Sedej, Anže Hubman, Franci Merzel, Kolektivna Langevinova dinamika počasnih gibanj v biomolekularnih sistemih., 13. konferenca fizikov v osnovnih raziskavah : zbornik povzetkov : Brdo pri Kranju, 18. november 2024. Ljubljana: Fakulteta za matematiko in fiziko, 2024. Str. 59. https://konfor.fmf.uni-lj.si/wp-content/uploads/2024/11/KONFOR24.pdf.
