Molekulardynamik-Simulation photoinduzierter intramolekularer Signalübertragung in Proteinen

• Antragsteller: Professor Dr. Gerhard Stock
• Fachliche Zuordnung: Theoretische Chemie: Elektronenstruktur, Dynamik, Simulation
• Förderung: Förderung von 2012 bis 2023
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 218648086

• Erstellungsjahr: 2024

Zusammenfassung der Projektergebnisse

The propagation of energetic and conformational changes in a protein, in other words, energy transfer and intramolecular signaling, plays a vital role in biomolecular function. In spite of its importance as elementary process of cell signaling as well as target in pharmaceutical research, there is surprisingly little known about the underlying dynamical process of allosteric communication. To facilitate the interpretations of recent timeresolved infrared experiments on photoswitchable proteins, we performed extensive molecular dynamics (MD) simulations, including standard equilibrium studies for basic structural characterization, enhanced sampling techniques to study the free energy landscape, and nonequilibrium MD to model the photoinduced transport process. We focused on three topics. Firstly, inspired by recent experimental data of the energy transport in various proteins, we performed nonequilibrium MD simulations and master equation modeling of the sitespecific energy flow in these systems, and investigate the pathways of the intramolecular and intermolecular energy transport. Secondly, we performed extensive MD simulations of allosteric perturbation experiments on various PDZ domains and RNaseA, where the protein response is measured subsequent to switching the binding affinity of the ligand. By analyzing the time evolution of the nonequilibrium trajectories, we uncovered the microscopic mechanisms underlying the process. Moreover, we performed large-scale simulations of the heat-shock protein Hsp90 to reveal the hierarchical dynamics in this system and compared to single-molecule FRET experiments. Thirdly, to deal with the huge amount of data provided by nonequilibrium MD simulations, we extended recent formulations of Langevin equation and Markov state modeling. In particular, we discussed the Langevin modeling of non-Markovian data and developed the algorithm MSMPathfinder, which allows to find all relevant pathways and their correct weights and associated waiting times with predefined accuracy.

Projektbezogene Publikationen (Auswahl)

• Allostery in Its Many Disguises: From Theory to Applications. Structure, 27(4), 566-578.
  Wodak, Shoshana J.; Paci, Emanuele; Dokholyan, Nikolay V.; Berezovsky, Igor N.; Horovitz, Amnon; Li, Jing; Hilser, Vincent J.; Bahar, Ivet; Karanicolas, John; Stock, Gerhard; Hamm, Peter; Stote, Roland H.; Eberhardt, Jerome; Chebaro, Yassmine; Dejaegere, Annick; Cecchini, Marco; Changeux, Jean-Pierre; Bolhuis, Peter G.; Vreede, Jocelyne ... & McLeish, Tom
  
• Energy Transport Pathways in Proteins: A Non-equilibrium Molecular Dynamics Simulation Study. Journal of Chemical Theory and Computation, 15(10), 5750-5757.
  Gulzar, Adnan; Valiño, Borau Luis; Buchenberg, Sebastian; Wolf, Steffen & Stock, Gerhard
  
• Photocontrolling Protein–Peptide Interactions: From Minimal Perturbation to Complete Unbinding. Journal of the American Chemical Society, 141(27), 10702-10710.
  Jankovic, Brankica; Gulzar, Adnan; Zanobini, Claudio; Bozovic, Olga; Wolf, Steffen; Stock, Gerhard & Hamm, Peter
  
• Master equation model to predict energy transport pathways in proteins. The Journal of Chemical Physics, 152(4).
  Valiño-Borau, Luis; Gulzar, Adnan & Stock, Gerhard
  
• Modeling non-Markovian data using Markov state and Langevin models. The Journal of Chemical Physics, 153(24).
  Lickert, Benjamin & Stock, Gerhard
  
• MSMPathfinder: Identification of Pathways in Markov State Models. Journal of Chemical Theory and Computation, 16(12), 7874-7882.
  Nagel, Daniel; Weber, Anna & Stock, Gerhard
  
• Real-time observation of ligand-induced allosteric transitions in a PDZ domain. Proceedings of the National Academy of Sciences, 117(42), 26031-26039.
  Bozovic, Olga; Zanobini, Claudio; Gulzar, Adnan; Jankovic, Brankica; Buhrke, David; Post, Matthias; Wolf, Steffen; Stock, Gerhard & Hamm, Peter
  
• Vibrational Spectroscopic Map, Vibrational Spectroscopy, and Intermolecular Interaction. Chemical Reviews, 120(15), 7152-7218.
  Baiz, Carlos R.; Błasiak, Bartosz; Bredenbeck, Jens; Cho, Minhaeng; Choi, Jun-Ho; Corcelli, Steven A.; Dijkstra, Arend G.; Feng, Chi-Jui; Garrett-Roe, Sean; Ge, Nien-Hui; Hanson-Heine, Magnus W. D.; Hirst, Jonathan D.; Jansen, Thomas L. C.; Kwac, Kijeong; Kubarych, Kevin J.; Londergan, Casey H.; Maekawa, Hiroaki; Reppert, Mike; Saito, Shinji ... & Zanni, Martin T.
  
• Hierarchical dynamics in allostery following ATP hydrolysis monitored by single molecule FRET measurements and MD simulations. Chemical Science, 12(9), 3350-3359.
  Wolf, Steffen; Sohmen, Benedikt; Hellenkamp, Björn; Thurn, Johann; Stock, Gerhard & Hugel, Thorsten
  
• Through bonds or contacts? Mapping protein vibrational energy transfer using non-canonical amino acids. Nature Communications, 12(1).
  Deniz, Erhan; Valiño-Borau, Luis; Löffler, Jan G.; Eberl, Katharina B.; Gulzar, Adnan; Wolf, Steffen; Durkin, Patrick M.; Kaml, Robert; Budisa, Nediljko; Stock, Gerhard & Bredenbeck, Jens
  
• Energy Transport and Its Function in Heptahelical Transmembrane Proteins. The Journal of Physical Chemistry B, 126(43), 8735-8746.
  Helmer, Nadja; Wolf, Steffen & Stock, Gerhard