TY - JOUR A1 - Schulz, Robert A1 - Yamamoto, Kenji A1 - Klossek, André A1 - Rancan, Fiorenza A1 - Vogt, Annika A1 - Schütte, Christof A1 - Rühl, Eckart A1 - Netz, Roland R. T1 - Modeling of Drug Diffusion Based on Concentration Profiles in Healthy and Damaged Human Skin JF - Biophysical Journal N2 - Based on experimental drug concentration profiles in healthy as well as tape-stripped ex vivo human skin, we model the penetration of the antiinflammatory drug dexamethasone into the skin layers by the one-dimensional generalized diffusion equation. We estimate the position-dependent free-energy and diffusivity profiles by solving the conjugated minimization problem, in which the only inputs are concentration profiles of dexamethasone in skin at three consecutive penetration times. The resulting free-energy profiles for damaged and healthy skin show only minor differences. In contrast, the drug diffusivity in the first 10 μm of the upper skin layer of damaged skin is 200-fold increased compared to healthy skin, which reflects the corrupted barrier function of tape-stripped skin. For the case of healthy skin, we examine the robustness of our method by analyzing the behavior of the extracted skin parameters when the number of input and output parameters are reduced. We also discuss techniques for the regularization of our parameter extraction method. Y1 - 2019 U6 - https://doi.org/10.1016/j.bpj.2019.07.027 VL - 117 IS - 5 SP - 998 EP - 1008 ER - TY - JOUR A1 - Straube, Arthur A1 - Kowalik, Bartosz G. A1 - Netz, Roland R. A1 - Höfling, Felix T1 - Rapid onset of molecular friction in liquids bridging between the atomistic and hydrodynamic pictures JF - Commun. Phys. N2 - Friction in liquids arises from conservative forces between molecules and atoms. Although the hydrodynamics at the nanoscale is subject of intense research and despite the enormous interest in the non-Markovian dynamics of single molecules and solutes, the onset of friction from the atomistic scale so far could not be demonstrated. Here, we fill this gap based on frequency-resolved friction data from high-precision simulations of three prototypical liquids, including water. Combining with theory, we show that friction in liquids emerges abruptly at a characteristic frequency, beyond which viscous liquids appear as non-dissipative, elastic solids. Concomitantly, the molecules experience Brownian forces that display persistent correlations. A critical test of the generalised Stokes–Einstein relation, mapping the friction of single molecules to the visco-elastic response of the macroscopic sample, disproves the relation for Newtonian fluids, but substantiates it exemplarily for water and a moderately supercooled liquid. The employed approach is suitable to yield insights into vitrification mechanisms and the intriguing mechanical properties of soft materials. Y1 - 2020 U6 - https://doi.org/10.1038/s42005-020-0389-0 VL - 3 SP - 126 PB - Nature ER - TY - JOUR A1 - Khatri, Vinod A1 - Boback, Nico A1 - Abdelwahab, Hassan A1 - Niemeyer, Daniela A1 - Palmer, Tahlia M. A1 - Sahoo, Anil Kumar A1 - Kerkhoff, Yannic A1 - Ludwig, Kai A1 - Balci, Dilara A1 - Trimpert, Jakob A1 - Haag, Rainer A1 - Povolotsky, Tatyana L. A1 - Netz, Roland R. A1 - Drosten, Christian A1 - Lauster, Daniel C. A1 - Bhatia, Sumati T1 - Polysialosides outperform sulfated analogs for the inhibition of SARS-CoV-2 JF - Small N2 - Both polysialosides and polysulfates are known to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. However, a comprehensive site by site analysis of their binding affinities and potential synergistic antiviral effects have not been performed. Here, we report on the synthesis of polysialosides with nanomolar binding affinities to spike proteins of SARS-CoV-2 in solution using microscale thermophoresis (MST). The dendritic polyglycerol based polysialosides dPG500(SA)0.55 and dPG500(SA)0.25, with a dissociation constant Kd of 4.78 nM and 10.85 nM, respectively, bind ~500 times stronger than the high density polysulfated analog dPG500(OSO3Na)0.55, to intact SARS-CoV-2 virus particles or isolated spike protein. In fact, the presence of sulfate groups in a heteromultivalent compound dPG500(SA)0.20(OSO3Na)0.20 weakens the binding to spike proteins. A polycarboxylated analog does not bind to SARS-CoV-2, ruling out that the interaction of polysialoside is simply driven by electrostatic interactions. Furthermore, we found potent nanomolar binding of dPG500(SA)0.55 to SARS-CoV-2 variant B.1.617 (Delta) and B.1.1.529 (Omicron) RBD. Using explicit-solvent all-atom molecular dynamics (MD) simulations and docking studies, we obtain atomistic details on the interaction of different functional groups with the SARS-CoV-2 RBD and their binding affinities. Our data support the conclusion that sialosides interact stronger with RBD than sulfates. Notably, our most affine binder dPG500(SA)0.55 inhibits SARS-CoV-2 (WT, D614G) replication up to 98.6% at low nanomolar concentrations. Y1 - 2025 UR - https://doi.org/10.26434/chemrxiv-2024-8b0gb U6 - https://doi.org/10.1002/smll.202500719 VL - 21 IS - 34 ER -