Quantifying Protein Shape to Elucidate Its Influence on Solution Viscosity in High-Concentration Electrolyte...

Area of Science:

• Biochemistry
• Biophysics
• Materials Science

Background:

• High-concentration, low-viscosity therapeutic proteins are crucial for subcutaneous and local injections.
• Protein shape is a known factor influencing solution viscosity, but its precise impact is not fully quantified.
• Understanding protein shape's role is key to designing optimized protein therapeutics.

Purpose of the Study:

• To quantitatively determine the impact of protein shape on solution viscosity.
• To establish a correlation between protein shape and critical concentration (C*).
• To explore computational methods for predicting protein shape factors.

Main Methods:

• Experimentally determined shape factors (v) for seven model proteins using Einstein's viscosity theory.
• Correlated shape factors with protein structure data (crystal structures or AlphaFold predictions).
• Analyzed the relationship between protein shape and critical concentration (C*) in electrolyte solutions.

Main Results:

• Protein shape factors correlated strongly with the ratio of surface area to volume (SA/V^(2/3)).
• Computational estimation of protein shape factors from amino acid sequences is feasible.
• More spherical protein shapes increase critical concentration (C*) in high-concentration electrolyte solutions.

Conclusions:

• Protein shape is a primary determinant of therapeutic protein solution viscosity.
• Quantitative analysis provides insights into molecular engineering for viscosity optimization.
• Findings facilitate the design of improved protein therapeutics with desirable viscosity profiles.