When Diffusion Slows Down: How Crowding, Hydrodynamics, and Softness Shape Protein Motion

by Prof. Christian Gutt (University of Siegen)

Thursday 7 May 2026, 15:15 → 16:15 Europe/Stockholm

Biological environments are highly crowded, with macromolecular volume fractions often exceeding 30–40%. In such conditions, protein motion deviates strongly from simple Brownian diffusion, yet the physical mechanisms governing this behavior remain poorly understood due to a long-standing experimental gap at nanometer length scales and microsecond times. In this talk, I will present recent advances using megahertz X-ray photon correlation spectroscopy (MHz-XPCS) at X-ray free-electron lasers to directly probe protein dynamics in this previously inaccessible regime. These measurements reveal that protein motion in crowded environments is governed by a complex interplay of transient caging, hydrodynamic interactions, and particle softness, leading to anomalous, non-exponential relaxation dynamics. Across model systems ranging from globular proteins in polymeric crowders to native lipoproteins in dense biological fluids, we observe a strong coupling between structure and dynamics, including collective slowing-down at characteristic length scales and pronounced deviations from classical diffusion–viscosity relations. Together, these results establish a physical picture in which protein transport is controlled not only by excluded volume, but by interaction-specific effects and many-body hydrodynamics. This framework provides new insight into molecular motion in biological media and has implications for processes ranging from intracellular transport to drug delivery in complex fluids.

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Lipoprotein diffusion in dense yolk plasma is governed by softness, hydrodynamics, and caging: Insights from MHz-XPCS. PNAS 123, e2519681123 (2026)

Dargasz, M. et al.
Depletion-induced interactions modulate nanoscale protein diffusion in polymeric crowder solutions.
PNAS (2026, in review / draft)

Girelli, A. et al.
Coherent X-rays reveal anomalous molecular diffusion and cage effects in crowded protein solutions.
Nature Communications 16, 10814 (2025)

Reiser, M. et al.
Resolving molecular diffusion and aggregation of antibody proteins with megahertz X-ray free-electron laser pulses.
Nature Communications 13, 5528 (2022)