Screening Protein Conformational Responses by Molecular Friction Sensing
5 affiliations
- 1Bruker Dynamic Biosensors, Bruker Daltonics GmbH & Co. KG, Perchtinger Str. 8/10, Munich, Germany, 81379
- 2Kurt-Schwabe-Institut für Mess- und Sensortechnik Meinsberg e.V.
- 3Technical University Darmstadt, Karolinenplatz 5, Darmstadt, Germany, 64289
- 4Ludwig-Maximilians-Universität München, Butenandtstr. 5–13, Munich, Germany, 81377
- 5Technical University Dresden
Abstract
Small-molecule drugs often act by stabilizing specific protein conformations, yet most biophysical screening platforms report binding affinity or kinetics without directly capturing structural response. Here we introduce molecular friction sensing (MFS), a screening-compatible approach that detects ligand-induced changes in protein conformation through changes in hydrodynamic drag exerted on electrically switchable DNA origami nanolevers. Across a diverse protein panel and under physiological conditions, the method quantitatively reports protein size and resolves ligand-dependent conformational shifts with sub-Angström sensitivity. In maltodextrin-binding protein, cognate and non-cognate maltodextrins produced distinct friction signatures that mirrored their biological roles. In a carbonic anhydrase screen, molecular friction sensing identified compound-dependent conformational responses among SPR-validated binders, revealing that affinity and kinetics do not predict structural outcome. Molecular friction sensing therefore adds a structural dimension to interaction analysis and provides a route to prioritize drug candidates by the conformations they induce.
Related
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BibTeX
@misc{paseiro2026screening,
title = {{Screening Protein Conformational Responses by Molecular Friction Sensing}},
author = {Pablo Porragas Paseiro and Lukas Aufinger and Alfred Kick and Tereza Jahodová and Veronica Hamer and Ulrich Rant and Wouter Engelen},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15004867/v2},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15004867/v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Screening Protein Conformational Responses by Molecular Friction Sensing
AU - Pablo Porragas Paseiro
AU - Lukas Aufinger
AU - Alfred Kick
AU - Tereza Jahodová
AU - Veronica Hamer
AU - Ulrich Rant
AU - Wouter Engelen
PY - 2026
DA - 2026/09/29
PB - ChemRxiv
DO - 10.26434/chemrxiv.15004867/v2
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15004867/v2
AB - Small-molecule drugs often act by stabilizing specific protein conformations, yet most biophysical screening platforms report binding affinity or kinetics without directly capturing structural response. Here we introduce molecular friction sensing (MFS), a screening-compatible approach that detects ligand-induced changes in protein conformation through changes in hydrodynamic drag exerted on electrically switchable DNA origami nanolevers. Across a diverse protein panel and under physiological conditions, the method quantitatively reports protein size and resolves ligand-dependent conformational shifts with sub-Angström sensitivity. In maltodextrin-binding protein, cognate and non-cognate maltodextrins produced distinct friction signatures that mirrored their biological roles. In a carbonic anhydrase screen, molecular friction sensing identified compound-dependent conformational responses among SPR-validated binders, revealing that affinity and kinetics do not predict structural outcome. Molecular friction sensing therefore adds a structural dimension to interaction analysis and provides a route to prioritize drug candidates by the conformations they induce.
ER -