Molecular Insight into the Protein–Polymer Interactions in N-Terminal PEGylated Bovine Serum Albumin

Abstract

Therapeutic proteins have increasingly been used in modern medical applications, but their effectiveness is limited by factors such as stability and blood circulation time. Recently, there has been significant research into covalently linking polyethylene glycol polymer chains (PEG) to proteins, known as PEGylation, to mitigate these issues. In this work, an atomistic molecular dynamics study of N-terminal conjugated PEG-BSA (bovine serum albumin) was conducted with varying PEG molecular weights (2, 5, 10, and 20 kDa) to probe PEG-BSA interactions and evaluate the effect of polymer length on dynamics. It was found that the affinity of PEG toward the protein surface increased as a function of PEG molecular weight and that a certain weight (around 10 kDa) was required to promote protein–polymer interactions. Additionally, preferential interactions were monitored through formed contacts and hotspots were identified. PEG chains coordinating in looplike conformations were found near lysine residues. Also, it was found that hydrophobic interactions played an important role in promoting PEG-BSA interactions as the PEG molecular weight increased. The results provide insight into underlying mechanisms behind transitions in PEG conformations and will aid in future design of effective PEGylated drug molecules.

Molecular Insights into Site-Specific Interferon-α2a Bioconjugates Originated from PEG, LPG, and PEtOx

“…The protein–polymer interaction profiles (Figures S18 and S19) from our simulations differed for the type of polymer and the type of linker. With regard to BCN variants, PEG preferentially wrapped around positively charged lysines and arginines, as similarly observed before . In contrast, LPG was often situated near serines and methionines, whereas the hydrophobic PEtOx more readily interacted with aromatic residues (F, Y, H).…”

“…To further detail thermal stability and interaction profiles of the polymers and both cyclooctyne linkers on a molecular level, we conducted classical molecular dynamics simulations (cMDs) of the IFN-α2a WT and Gaussian accelerated MDs (GaMDs) , of IFNK31N 3 10 kDa BCN/DBCO bioconjugates. Similar to a previously published study, we modeled ten different starting structures of each variant in which the polymers covered different areas of the protein surface, followed by constrained network analyses (CNA) in which body-and-bar networks were generated from these structural ensembles. − , Constraints based on covalent and noncovalent interactions were evaluated to assess protein rigidity and, by successively releasing the ones resulting from hydrogen bonds and salt-bridges, unfolding temperatures were predicted. The output agreed with experimental findings (Figure A).…”

Solutions and Condensed Phases of PEG2000 from All-Atom Molecular Dynamics

“…Three properties, R g , D ee , and Z , change dramatically from 3.34, 11.01, and 0.38 to 0.71, 1.86, and 0.08 nm, respectively. This behavior is consistent with previous results in the gas phase and the chain-folded prolate spheroid structure R g is in agreement with other free macromolecule simulations . Meanwhile, NPT MD simulations at an average temperature of 300 K showed that PEG 2000 in two aqueous solutions collapsed into a similar prolate spheroid-like structure in about 3–5 ns, maintaining subsequent R g fluctuating values without major extensions over time.…”

“…This behavior is consistent with previous results in the gas phase 16 and the chain-folded prolate spheroid structure R g is in agreement with other free macromolecule simulations. 52 Meanwhile, NPT MD simulations at an average temperature of 300 K showed that PEG 2000 in two aqueous solutions collapsed into a similar prolate spheroid-like structure in about 3−5 ns, maintaining subsequent R g fluctuating values without major extensions over time. The relaxation toward equilibrium of both, the R g and D ee values, is depicted in Figure S3 of Supporting Information.…”

Biomolecular engineering of drugs loading in Riboflavin-targeted polymeric devices: simulation and experimental

“…To date, researchers have reported various aspects of polymeric NP interactions with biological membranes 10 , drugs 11 – 13 , peptides 14 , 15 , BSA 16 , and proteins 17 . Among different agents, polymer-drug interactions, especially anticancer drugs, have attracted attention recently 11 , 18 .…”