The Molecular Basis for Hydrodynamic Properties of PEGylated Human Serum Albumin

Abstract

Polyethylene glycol conjugation provides a protective modification that enhances the pharmacokinetics and solubility of proteins for therapeutic use. A knowledge of the structural ensemble of these PEGylated proteins is necessary to understand the molecular details that contribute to their hydrodynamic and colligative properties. Because of the large size and dynamic flexibility of pharmaceutically important PEGylated proteins, the determination of structure is challenging. Here we demonstrate that structural ensembles, generated by coarse-grained simulations, can be analyzed with HullRad and used to predict sedimentation coefficients and concentration dependent hydrodynamic and diffusion nonideality coefficients of PEGylated proteins. A knowledge of these properties enhances the ability to design and analyze new modified protein therapeutics. STATEMENT OF SIGNIFICANCEProteins constitute a growing class of biotherapeutics. Chemical modification(s) with inert polymers are known to enhance the serum half-life and formulation of these biological therapeutics but the effects of modification on protein-protein interactions in solution have been difficult to predict. Here we describe methods for predicting the molecular basis for the hydrodynamic properties of polymer conjugated proteins that determine their solution behavior.