Coherent X-rays reveal anomalous molecular diffusion and cage effects in crowded protein solutions

Anita Girelli (), Maddalena Bin, Mariia Filianina, Michelle Dargasz, Nimmi Das Anthuparambil, Johannes Möller, Alexey Zozulya, Iason Andronis, Sonja Timmermann, Sharon Berkowicz, Sebastian Retzbach, Mario Reiser, Agha Mohammad Raza, Marvin Kowalski, Mohammad Sayed Akhundzadeh, Jenny Schrage, Chang Hee Woo, Maximilian D. Senft, Lara Franziska Reichart, Aliaksandr Leonau, Prabhu Rajaiah Prince, William Chèvremont, Tilo Seydel, Jörg Hallmann, Angel Rodriguez-Fernandez, Jan-Etienne Pudell, Felix Brausse, Ulrike Boesenberg, James Wrigley, Mohamed Youssef, Wei Lu, Wonhyuk Jo, Roman Shayduk, Trey Guest, Anders Madsen, Felix Lehmkühler, Michael Paulus, Fajun Zhang, Frank Schreiber, Christian Gutt and Fivos Perakis ()
Additional contact information
Anita Girelli: AlbaNova University Center, Stockholm University, Department of Physics
Maddalena Bin: AlbaNova University Center, Stockholm University, Department of Physics
Mariia Filianina: AlbaNova University Center, Stockholm University, Department of Physics
Michelle Dargasz: Universität Siegen, Department Physik
Nimmi Das Anthuparambil: Universität Siegen, Department Physik
Johannes Möller: European X-Ray Free-Electron Laser Facility
Alexey Zozulya: European X-Ray Free-Electron Laser Facility
Iason Andronis: AlbaNova University Center, Stockholm University, Department of Physics
Sonja Timmermann: Universität Siegen, Department Physik
Sharon Berkowicz: AlbaNova University Center, Stockholm University, Department of Physics
Sebastian Retzbach: Universität Tübingen, Institut für Angewandte Physik
Mario Reiser: AlbaNova University Center, Stockholm University, Department of Physics
Agha Mohammad Raza: Universität Siegen, Department Physik
Marvin Kowalski: Universität Siegen, Department Physik
Mohammad Sayed Akhundzadeh: Universität Siegen, Department Physik
Jenny Schrage: Universität Siegen, Department Physik
Chang Hee Woo: TU Dortmund, Fakultät Physik/DELTA
Maximilian D. Senft: Universität Tübingen, Institut für Angewandte Physik
Lara Franziska Reichart: Universität Tübingen, Institut für Angewandte Physik
Aliaksandr Leonau: Universität Siegen, Department Physik
Prabhu Rajaiah Prince: The Hamburg Centre for Ultrafast Imaging
William Chèvremont: ESRF - The European Synchrotron
Tilo Seydel: Institut Laue-Langevin
Jörg Hallmann: European X-Ray Free-Electron Laser Facility
Angel Rodriguez-Fernandez: European X-Ray Free-Electron Laser Facility
Jan-Etienne Pudell: European X-Ray Free-Electron Laser Facility
Felix Brausse: European X-Ray Free-Electron Laser Facility
Ulrike Boesenberg: European X-Ray Free-Electron Laser Facility
James Wrigley: European X-Ray Free-Electron Laser Facility
Mohamed Youssef: European X-Ray Free-Electron Laser Facility
Wei Lu: European X-Ray Free-Electron Laser Facility
Wonhyuk Jo: European X-Ray Free-Electron Laser Facility
Roman Shayduk: European X-Ray Free-Electron Laser Facility
Trey Guest: European X-Ray Free-Electron Laser Facility
Anders Madsen: European X-Ray Free-Electron Laser Facility
Felix Lehmkühler: The Hamburg Centre for Ultrafast Imaging
Michael Paulus: TU Dortmund, Fakultät Physik/DELTA
Fajun Zhang: Universität Tübingen, Institut für Angewandte Physik
Frank Schreiber: Universität Tübingen, Institut für Angewandte Physik
Christian Gutt: Universität Siegen, Department Physik
Fivos Perakis: AlbaNova University Center, Stockholm University, Department of Physics

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Understanding protein motion within the cell is crucial for predicting reaction rates and macromolecular transport in the cytoplasm. A key question is how crowded environments affect protein dynamics through hydrodynamic and direct interactions at molecular length scales. Using megahertz X-ray Photon Correlation Spectroscopy (MHz-XPCS) at the European X-ray Free Electron Laser (EuXFEL), we investigate ferritin diffusion at microsecond time scales. Our results reveal anomalous diffusion, indicated by the non-exponential decay of the intensity autocorrelation function g2(q, t) at high concentrations. This behavior is consistent with the presence of cage-trapping between the short- and long-time protein diffusion regimes. Modeling with the δγ-theory of hydrodynamically interacting colloidal spheres successfully reproduces the experimental data by including a scaling factor linked to the protein direct interactions. These findings offer insights into the complex molecular motion in crowded protein solutions, with potential applications for optimizing ferritin-based drug delivery, where protein diffusion is the rate-limiting step.

Date: 2025
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DOI: 10.1038/s41467-025-66972-6

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