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Many cellular processes, such asthe diffusion of biomacromolecules,the movement of molecular motors, and the conformational dynamicsof proteins, are subjected to hydrodynamic forces because of the highviscosities of cellular environments. However, it is still unknownhow hydrodynamic forces are related to the physical properties ofdifferent viscogens. Here, using the atomic force microscope-basedforce spectroscopy technique, we directly measured the hydrodynamicforces acting on a moving cantilever in various viscogen solutions.We found that the hydrodynamic force is not only dependent on theviscosity but also related to the molecular weight of viscogens. Counterintuitively,at the same macroscopic viscosity, the hydrodynamic force rises withthe increasing molecular weight of viscogens, although the local microscopicviscosity of the solution decreases. This finding provides insightsinto the origin of hydrodynamic forces in biomolecule solutions andcould inspire many force-spectroscopy-based techniques to measurethe molecular weight and conformational changes of biomacromoleculesin biological settings directly. [ABSTRACT FROM AUTHOR]