Atomistic insight towards the impact of polymer architecture and grafting density on structure-dynamics of PEGylated bovine serum albumin and their applications

Abstract

Macromolecules such as proteins conjugated to polyethylene glycol (PEG) have been employed in therapeutic drug applications, and recent research has emphasized the potential of varying polymer architectures and conjugation strategies to achieve improved efficacy. In this study, we performed atomistic molecular dynamics simulations of bovine serum albumin (BSA) conjugated to 5 kDa PEG polymers in an array of schemes, including varied numbers of attached chains, grafting density, and nonlinear architectures. Nonlinear architectures included U-shaped PEG, Y-shaped PEG, and poly(oligoethylene glycol methacrylate) (POEGMA). Buried surface area calculations and polymer volume map analyses revealed that volume exclusion behaviors of the high grafting density conjugate promoted additional protein–polymer interactions when compared to simply increasing numbers of conjugated chains uniformly across the protein surface. Investigation of nonlinear polymer architectures showed that stable polymer-lysine loop-like conformations seen in previous conjugate designs were more variable in prevalence, especially in POEGMA, which contained short oligomer PEG chains. The findings of this comprehensive study of alternate PEGylation schemes of BSA provide critical insight into molecular patterns of interaction within bioconjugates and highlight their importance in the future of controlled modification of conjugate system parameters.

Molecular Dynamics Simulations for Rationalizing Polymer Bioconjugation Strategies: Challenges, Recent Developments, and Future Opportunities

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Protein PEGylation: Navigating Recombinant Protein Stability, Aggregation, and Bioactivity

“…Previously, [13] discovered that the secondary structure motif is not specifically responsible for PEG to induce protein stability. Alternatively, the orientation PEG appeared to be the most influential factor inducing stability [14]. Furthermore, the study conducted by Abuchowski et al (1977) proclaimed that amino acid side chains are available for conjugation [15].…”

“…It was preferably selected due to its two folding energetic states, which have been significantly characterized and allowed amino acid substitutions at many locations. The WW protein has 34 residues that assist their preparation via solid-phase synthesis of peptides, thus simplifying the linkage of shorter PEG oligomer at a single location [ 14 ]. The PEG consisting four ethylene oxide units was attached at position 19 of a single Asn side chain of the WW domain of the human protein.…”

Molecular Insights into the Improved Bioactivity of Interferon Conjugates Attached to a Helical Polyglutamate

“…How can the attached helical polypeptide prevent the formation of complexes for IFN with other proteins? Such microscopic questions are suitable to be explored via molecular simulation. − For example, the attached coiled polymer/polypeptide is revealed to encapsulate the target protein, and sometimes allosterically change the latter’s structure . In previous simulation work, , we showed that, in delivering therapeutic proteins, the hydrophilic zwitterionic peptides with the highest contact preference could be a potential choice.…”