Physical Basis Of pKa Shift For Ionizable Lipids In An LNP-like Environment
- 1University of Rochester Medical Center
Abstract
Lipid nanoparticles (LNPs) are a leading drug delivery platform for mRNA or other nucleic acid-based therapeutics. LNP platforms are typically composed of ionizable aminolipids, phospholipids, sterols, and lipids tagged with polyethylene glycol. The ionizable aminolipids are typically cationic at low pH, allowing them to encapsulate negatively charged mRNA. The pH at which the ionizable head groups change charge states, the apparent pKa, is crucial to understand the characteristics and formulation of LNP. However, this is difficult to measure as the apparent pKa differs from the pKa of the aminolipids in bulk solution due to the complex chemical and charge environment. In this study, we use molecular dynamics (MD) simulations with alchemical free energy perturbation to calculate the pKa shift as a function of lipid composition, treating LNP-like and vesicle-like environments. Our results show that the pH-dependent structure of the systems affects the trends in pKa shifts in complex ways, driven by factors including surface electrostatics and lipid internalization. Our all-atom simulation protocol allows us to efficiently estimate the apparent pKa of LNP-like models formed with novel ionizable aminolipids and estimate how it will change with composition.
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BibTeX
@misc{sharma2026physical,
title = {{Physical Basis Of pKa Shift For Ionizable Lipids In An LNP-like Environment}},
author = {A. Sharma and S. Sur and A. Grossfield},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.07.757025},
url = {https://www.biorxiv.org/content/10.64898/2026.10.07.757025v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Physical Basis Of pKa Shift For Ionizable Lipids In An LNP-like Environment
AU - A. Sharma
AU - S. Sur
AU - A. Grossfield
PY - 2026
DA - 2026/10/07
PB - bioRxiv
DO - 10.64898/2026.10.07.757025
UR - https://www.biorxiv.org/content/10.64898/2026.10.07.757025v1
AB - Lipid nanoparticles (LNPs) are a leading drug delivery platform for mRNA or other nucleic acid-based therapeutics. LNP platforms are typically composed of ionizable aminolipids, phospholipids, sterols, and lipids tagged with polyethylene glycol. The ionizable aminolipids are typically cationic at low pH, allowing them to encapsulate negatively charged mRNA. The pH at which the ionizable head groups change charge states, the apparent pKa, is crucial to understand the characteristics and formulation of LNP. However, this is difficult to measure as the apparent pKa differs from the pKa of the aminolipids in bulk solution due to the complex chemical and charge environment. In this study, we use molecular dynamics (MD) simulations with alchemical free energy perturbation to calculate the pKa shift as a function of lipid composition, treating LNP-like and vesicle-like environments. Our results show that the pH-dependent structure of the systems affects the trends in pKa shifts in complex ways, driven by factors including surface electrostatics and lipid internalization. Our all-atom simulation protocol allows us to efficiently estimate the apparent pKa of LNP-like models formed with novel ionizable aminolipids and estimate how it will change with composition.
ER -