(548g) Molecular Modeling of Protein Transport in Polymer-Grafted Ion Exchangers

Ion exchange matrices containing charged grafted polymers have been shown to provide both increased protein binding capacity and faster protein adsorption kinetics as compared to traditional macroporous matrices. Experimental evidence of such improved characteristics has been obtained from macroscopic measurement of the rate of protein adsorption, and from intraparticle protein concentration profiles observed by confocal microscopy. Both of these measurements demonstrate that not only the rate, but also the mechanism of protein transport in these materials, is drastically different from ordinary pore-diffusion, exhibiting a different dependence on protein molecular size and concentration, salt concentration, and buffer type. However, the reasons behind these observations are not fully understood. Additional investigation is necessary to study the molecular mechanisms by which adsorption is facilitated in these systems.

In this work, we use molecular dynamics simulations to model a surface coated with a charged grafted polymer, as well as the interactions between this matrix and model proteins. We use coarse-grained representations of the polymer chains and proteins, along with an implicit solvent environment, as we are primarily interested in dynamical processes occurring over long length scales with respect to individual atoms. The polymer matrix is composed of chains representing dextran functionalized with sulfate groups to different extents (from 5% to 20% of the chain), and grafted to the surface at various densities (from 25 to 81 nm² per chain). We simulate the matrix in the absence of proteins, as well as with different concentrations of model lysozyme proteins interacting with the matrix.

Simulations of the grafted polymers alone, under a variety of experimental conditions, were used to validate the behavior of the model. The effective height of the grafted layer increases with increased graft density and the charge content of the dextran chains. We also explore the effects of different ionic strengths, represented by tuning the strength of electrostatics by the use of a reaction-field with separate short range and long range dielectric constants.

We estimate how the protein diffusivity varies with concentration, and investigate whether there is a critical concentration at which higher loadings significantly diminish the transport rate. We vary the effective ionic strength by tuning the dielectric constants, and vary the pH by tuning the surface charge on the protein, to determine how these factors affect protein diffusion through the matrix. Finally, we analyze the radial distribution functions to better understand the mechanism by which proteins interact with the chains. Molecular insights from this work are compared qualitatively with experimental measurements, and should aid in the optimization and design of future ion-exchange materials that utilize charged polymer grafts to facilitate protein adsorption and transport.