Chemical physics

Transient (computer programming)

Biology

Cytosol

Stokes radius

Globular protein

Operating system

Biochemistry

Molecule

Thermal diffusivity

Computer science

Physical chemistry

Thermodynamics

Physics

Organic chemistry

Diffusion

Cluster (spacecraft)

Rotational diffusion

Aqueous solution

Enzyme

Micelle

Crystallography

Chemistry

Programming language

Viscosity

Hydrodynamic radius

Biophysics

Size-exclusion chromatography

Proceedings of the National Academy of Sciences

We develop a detailed description of protein translational and rotational diffusion in concentrated solution on the basis of all-atom molecular dynamics simulations in explicit solvent. Our systems contain up to 540 fully flexible proteins with 3.6 million atoms. In concentrated protein solutions (100 mg/mL and higher), the proteins ubiquitin and lysozyme, as well as the protein domains third IgG-binding domain of protein G and villin headpiece, diffuse not as isolated particles, but as members of transient clusters between which they constantly exchange. A dynamic cluster model nearly quantitatively explains the increase in viscosity and the decrease in protein diffusivity with protein volume fraction, which both exceed the predictions from widely used colloid models. The Stokes-Einstein relations for translational and rotational diffusion remain valid, but the effective hydrodynamic radius grows linearly with protein volume fraction. This increase follows the observed increase in cluster size and explains the more dramatic slowdown of protein rotation compared with translation. Baxter's sticky-sphere model of colloidal suspensions captures the concentration dependence of cluster size, viscosity, and rotational and translational diffusion. The consistency between simulations and experiments for a diverse set of soluble globular proteins indicates that the cluster model applies broadly to concentrated protein solutions, with equilibrium dissociation constants for nonspecific protein-protein binding in the Kd ≈ 10-mM regime.

Dynamic cluster formation determines viscosity and diffusion in dense protein solutions