Recent light scattering studies have revealed the existence of two major structures in PEGylated proteins: polymer chains wrapping around the protein, with favorable interactions with its surface; or polymer chains following a Gaussian random coil conformation from the conjugation site on the protein surface. The differences in these observations, together with molecular simulation studies of plasma proteins in polyethylene glycol (PEG) solutions, suggest that PEG interactions with a protein may occur in a protein-dependent manner. We recently developed a new coarse-grained (CG) model for PEG in which the nonbonded interactions with amino acids were characterized utilizing state-of-the-art quantum mechanics calculations of interaction energies. In this work, the CG model is employed to test the MW dependency of wrapped/unwrapped structures for various PEGylated proteins via enhanced sampling techniques. In particular, the conformational space of PEGylated bovine serum albumin, chicken egg lysozyme, and human growth hormone were explored employing CG molecular dynamics and metadynamics to locate minimum energy structures of these bioconjugates in the relevant projections of the multidimensional free energy surfaces. We found that the surface conformational landscape of proteins dictates the binding properties of PEG chains toward individual amino acids. The amino acid composition of the protein surface is shown to promote the formation of wrapped structures for PEGylated hemoglobin in contrast with other proteins studied.

Efficient exploration of the conformational space for PEGylated proteins through biased coarse-grained molecular dynamics

2019 Spring National Meeting

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