Mechanistic Insights into Poloxamer 188–Mediated Stabilization of AAV8 Capsids Using Coarse-Grained Molecular Dynamics
5 affiliations
- 1Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 69 N. Eagleville Road, Storrs, CT 06269 USA
- 2Department of Computer Science, School of Computing, University of Connecticut, 69 N. Eagleville Road, Storrs, CT 06269 USA
- 3Department of Chemical & Biomolecular Engineering, University of Connecticut, 69 N. Eagleville Road, Storrs, CT 06269 USA
- 4Biopharmaceutical Innovation, Sarepta Therapeutics, Cambridge, MA 02142 USA
- 5Institute of Material Sciences (IMS), University of Connecticut, 69 N. Eagleville Road, Storrs, CT 06269 USA
Abstract
Purpose: Aggregation of adeno-associated virus (AAV) during manufacturing and storage remains a challenge in gene therapy formulation. This study evaluates how varying Poloxamer188 (P188) concentrations affect the structural stability and aggregation behavior of two full AAV8 capsids.
Methods: Coarse-grained molecular dynamics simulations of AAV8 capsids with P188 were performed for 4000 ns at 300 K. Center-of-mass (COM) separation, residue-level contacts, surface coverage, van der Waals interactions, radius of gyration (Rg), relative shape anisotropy (k2), and simulation snapshots were analyzed.
Results: Persistent capsid association was not observed in systems containing 10 or 24 P188 molecules (0.15% and 0.35% w/v), whereas systems containing 2 or 5 P188 molecules (0.03% and 0.07% w/v) showed delayed association relative to the surfactant-free system. Capsid surface coverage increased with P188 loading. Polyethylene oxide (EO) segments associated with the capsid surface early and persistently, followed by gradual polypropylene oxide (PO) engagement, indicating a preferential/sequential interaction mechanism. Higher P188 loadings showed negligible van der Waals attraction, consistent with steric shielding. Chain-resolved Rg and k2 profiles indicated initial conformational rearrangement followed by stabilization of distinct surface-associated P188 conformations, with varying spatial extension and shape anisotropy.
Conclusions: These findings provide mechanistic insight into the stabilizing effect of P188 on AAV via concentration-dependent surface coverage and steric hindrance that minimize capsid-capsid interactions associated with aggregation. The reported concentrations are nominal finite-box values defined by discrete P188 molecule counts and represent comparative simulation conditions rather than experimentally derived formulation thresholds. These findings provide a molecular basis for understanding P188-mediated AAV stabilization and for guiding formulation optimization.
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BibTeX
@article{sharifi2026mechanistic,
title = {{Mechanistic Insights into Poloxamer 188–Mediated Stabilization of AAV8 Capsids Using Coarse-Grained Molecular Dynamics}},
author = {Leila Sharifi and Jahanbakhsh Ghasemi and Leo Santisi and Shivangi Naik and Willow DiLuzio and Arani Chanda and Bodhisattwa Chaudhuri},
journal = {Pharmaceutical Research},
year = {2026},
month = sep,
doi = {10.1007/s11095-026-04187-0},
url = {https://doi.org/10.1007/s11095-026-04187-0},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Mechanistic Insights into Poloxamer 188–Mediated Stabilization of AAV8 Capsids Using Coarse-Grained Molecular Dynamics
AU - Leila Sharifi
AU - Jahanbakhsh Ghasemi
AU - Leo Santisi
AU - Shivangi Naik
AU - Willow DiLuzio
AU - Arani Chanda
AU - Bodhisattwa Chaudhuri
PY - 2026
DA - 2026/09/22
JO - Pharmaceutical Research
DO - 10.1007/s11095-026-04187-0
UR - https://doi.org/10.1007/s11095-026-04187-0
AB - Purpose: Aggregation of adeno-associated virus (AAV) during manufacturing and storage remains a challenge in gene therapy formulation. This study evaluates how varying Poloxamer188 (P188) concentrations affect the structural stability and aggregation behavior of two full AAV8 capsids. Methods: Coarse-grained molecular dynamics simulations of AAV8 capsids with P188 were performed for 4000 ns at 300 K. Center-of-mass (COM) separation, residue-level contacts, surface coverage, van der Waals interactions, radius of gyration (Rg), relative shape anisotropy (k2), and simulation snapshots were analyzed. Results: Persistent capsid association was not observed in systems containing 10 or 24 P188 molecules (0.15% and 0.35% w/v), whereas systems containing 2 or 5 P188 molecules (0.03% and 0.07% w/v) showed delayed association relative to the surfactant-free system. Capsid surface coverage increased with P188 loading. Polyethylene oxide (EO) segments associated with the capsid surface early and persistently, followed by gradual polypropylene oxide (PO) engagement, indicating a preferential/sequential interaction mechanism. Higher P188 loadings showed negligible van der Waals attraction, consistent with steric shielding. Chain-resolved Rg and k2 profiles indicated initial conformational rearrangement followed by stabilization of distinct surface-associated P188 conformations, with varying spatial extension and shape anisotropy. Conclusions: These findings provide mechanistic insight into the stabilizing effect of P188 on AAV via concentration-dependent surface coverage and steric hindrance that minimize capsid-capsid interactions associated with aggregation. The reported concentrations are nominal finite-box values defined by discrete P188 molecule counts and represent comparative simulation conditions rather than experimentally derived formulation thresholds. These findings provide a molecular basis for understanding P188-mediated AAV stabilization and for guiding formulation optimization.
SN - 0724-8741
SN - 1573-904X
ER -