Development of A Modeling Framework for Characterizing Protein–Polymer Bioconjugates with Enhanced Sampling Molecular Dynamics Simulations
5 affiliations
- 1Department of Chemical & Biological Engineering
- 2University of Colorado
- 3Materials Science & Engineering Program
- 4Department of Chemical Engineering
- 5University of Florida
Abstract
Protein–polymer bioconjugates represent a class of biomaterials that leverages the molecular specificity of proteins and the tunability of synthetic polymers. Strategic conjugation of polymers to protein surfaces can enhance key biomolecular properties such as structural stability and target affinity while preserving the biological functions of the native protein. The rational design of these hybrid biomolecules demands a detailed understanding of the underlying molecular mechanisms governing protein–polymer interfacial behavior. Critically, strong interfacial interactions can impose substantial energetic barriers that hinder conformational sampling in molecular dynamics (MD) studies of this system. Enhanced sampling methods are highly effective for overcoming such limitations in the simulation of biomolecular interfaces. However, the opportunity to apply enhanced sampling methods toward navigating the complex interfacial landscapes of protein–polymer bioconjugates has yet to be realized by the field. In this study, we showcase the development of a molecular modeling framework that leverages enhanced sampling to extensively characterize protein–polymer bioconjugates. To validate this framework, we constructed two bioconjugate models of hen egg-white lysozyme grafted with activated methoxy polyethylene glycol (mPEG) chains of varying lengths at multiple surface-exposed lysine sites. We then performed all-atom MD simulations of these PEGylated constructs, augmented with well-tempered metadynamics (WTM) to fully explore their conformational landscapes under multi-site polymer conjugation. This approach yielded converged free energy surfaces (FES) characterizing the thermodynamic favorability of grafted mPEG chain conformations at each conjugation site. We also identified key protein contact residues and site-specific non-bonded interactions responsible for bioconjugate stabilization. This study demonstrates a novel application of enhanced sampling methodologies in bioconjugate systems for characterizing site-specific conjugation effects on protein–polymer interfacial energetics and structural dynamics in the context of protein surface chemistry. More broadly, applying this methodological framework across diverse polymer chemistries and protein variants can elucidate molecular design rules for engineering bioconjugates with precise properties and functions for applications spanning biotechnology, energy, and health.
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BibTeX
@misc{dong2026development,
title = {{Development of A Modeling Framework for Characterizing Protein–Polymer Bioconjugates with Enhanced Sampling Molecular Dynamics Simulations}},
author = {Ziyue Dong and Aidan B. Wegner and David Saeb and Matthew M. C. Kwan and Pedro E. Cintrón Baerga and C. Wyatt Shields and Michael R. Shirts and Kayla G. Sprenger},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15004571/v3},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15004571/v3},
note = {CC BY},
}
RIS
TY - UNPB
TI - Development of A Modeling Framework for Characterizing Protein–Polymer Bioconjugates with Enhanced Sampling Molecular Dynamics Simulations
AU - Ziyue Dong
AU - Aidan B. Wegner
AU - David Saeb
AU - Matthew M. C. Kwan
AU - Pedro E. Cintrón Baerga
AU - C. Wyatt Shields
AU - Michael R. Shirts
AU - Kayla G. Sprenger
PY - 2026
DA - 2026/10/09
PB - ChemRxiv
DO - 10.26434/chemrxiv.15004571/v3
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15004571/v3
AB - Protein–polymer bioconjugates represent a class of biomaterials that leverages the molecular specificity of proteins and the tunability of synthetic polymers. Strategic conjugation of polymers to protein surfaces can enhance key biomolecular properties such as structural stability and target affinity while preserving the biological functions of the native protein. The rational design of these hybrid biomolecules demands a detailed understanding of the underlying molecular mechanisms governing protein–polymer interfacial behavior. Critically, strong interfacial interactions can impose substantial energetic barriers that hinder conformational sampling in molecular dynamics (MD) studies of this system. Enhanced sampling methods are highly effective for overcoming such limitations in the simulation of biomolecular interfaces. However, the opportunity to apply enhanced sampling methods toward navigating the complex interfacial landscapes of protein–polymer bioconjugates has yet to be realized by the field. In this study, we showcase the development of a molecular modeling framework that leverages enhanced sampling to extensively characterize protein–polymer bioconjugates. To validate this framework, we constructed two bioconjugate models of hen egg-white lysozyme grafted with activated methoxy polyethylene glycol (mPEG) chains of varying lengths at multiple surface-exposed lysine sites. We then performed all-atom MD simulations of these PEGylated constructs, augmented with well-tempered metadynamics (WTM) to fully explore their conformational landscapes under multi-site polymer conjugation. This approach yielded converged free energy surfaces (FES) characterizing the thermodynamic favorability of grafted mPEG chain conformations at each conjugation site. We also identified key protein contact residues and site-specific non-bonded interactions responsible for bioconjugate stabilization. This study demonstrates a novel application of enhanced sampling methodologies in bioconjugate systems for characterizing site-specific conjugation effects on protein–polymer interfacial energetics and structural dynamics in the context of protein surface chemistry. More broadly, applying this methodological framework across diverse polymer chemistries and protein variants can elucidate molecular design rules for engineering bioconjugates with precise properties and functions for applications spanning biotechnology, energy, and health.
ER -