Quantitative description of protein configuration and viscoelasticity using first-principles hydrodynamics applied to quartz crystal microbalance experiments

Abstract

The quartz crystal microbalance (QCM) is one of the few label-free techniques capable of sampling the response of proteins and their aggregates. However, QCM signals come encrypted by a complicated interaction between the biomolecular viscoelastic response and their hydrodynamic perturbations. This has hampered the quantitative interpretation of QCM signals of biomolecules. In addition, the large size disparity between proteins and the QCM flow penetration length of 100 nm creates a deadlock for standard simulation packages. Using first-principles modeling and adaptive schemes, we show that the ultrasensitive QCM sensor can be upgraded to a high-precision quantitative tool for protein analysis. We present a “Virtual-QCM” (VQCM) framework to introduce viscoelastic structures in a hydrodynamic solver for semi-infinite wall-bounded oscillatory flow. The fluid solver [R. P. Peláez, P. Palacios-Alonso, and R. Delgado-Buscalioni, J. Fluid Mech. 1010, A57 (2025)] is spectral in time and space and implements open boundaries focusing on the relevant fluid layer around proteins with ∼104 speed-up. Biomolecules are modeled as viscoelastic networks connected to the atomistic level via coarse-graining theory. Integrating VQCM with experiments allows us to predict the physicochemical properties of FtsZ and ZipA; bacterial proteins with intrinsically disordered regions (IDRs) tethered to lipid membrane substrates. Quantitative match with experiments at all coverages permits us to measure substrate binding affinities, IDR extension ℓ, stiffness k, and intrinsic friction ξ. We find the polypeptide chains to be extremely sensitive to the buffer ionic strength, with protein friction affected by Mg+2. Measured intrinsic relaxation times ξ/k ∼ [3–30] ns are consistent with FRET analyses. Access to microscopic information using standard QCM sensors will help decipher the IDR structure–function and other protein aggregates.