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Updated: Jun 28, 2026
07:31
Realistic Membrane Modeling Using Complex Lipid Mixtures in Simulation Studies
Published on: September 1, 2023
Membrane environment sets the functional pKa of ionizable lipids
Marius F W Trollmann1, Paolo Rossetti2, Rainer A Böckmann3
1Computational Biology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Erlangen National High-Performance Computing Center (NHR@FAU), Erlangen, Germany.
Biophysical Journal
|June 27, 2026
Summary
Ionizable aminolipids in lipid nanoparticles (LNPs) have lower apparent pKa values in membranes, influencing cargo release. Membrane composition and aminolipid structure dictate protonation and pH-dependent membrane remodeling for improved LNP delivery.
Area of Science:
- Biochemistry
- Materials Science
- Computational Chemistry
Background:
- Ionizable aminolipids are crucial for nucleic acid encapsulation and release by lipid nanoparticles (LNPs).
- A significant discrepancy exists between the effective acidic LNP pKa and the intrinsic basic pKa of aminolipids, which is not well understood.
- Understanding this pKa difference is key to optimizing LNP formulation for effective drug delivery.
Purpose of the Study:
- To quantify how aminolipid structure and membrane composition jointly influence aminolipid protonation and pH-dependent membrane remodeling.
- To investigate the discrepancy between intrinsic and apparent pKa values of widely used aminolipids in LNP-relevant membranes.
- To provide insights into how LNP formulation affects pKa and membrane remodeling for enhanced delivery performance.
Main Methods:
- Microsecond constant-pH molecular dynamics simulations were performed.
- Simulations included five common aminolipids (DODAP, DLin-MC3-DMA, DLin-KC2-DMA, ALC-0315, SM-102).
- Simulations utilized LNP-relevant ternary membranes composed of DOPC, DSPC, and cholesterol.
Main Results:
- Membrane embedding significantly lowers the apparent aminolipid pKa to physiologically relevant values (6-7.5), with shifts up to 3.5 pKa units.
- pH-driven membrane remodeling varies by aminolipid type: polyunsaturated lipids translocate, branched lipids form surface domains, and DODAP remains interfacially anchored.
- Saturated helper lipids (DSPC) enhance domain segregation and amplify pKa shifts compared to unsaturated lipids (DOPC).
Conclusions:
- Membrane phase behavior is a primary regulator of aminolipid protonation equilibria.
- Aminolipid structure and membrane composition jointly govern pKa and pH-dependent membrane remodeling.
- These findings offer a mechanistic basis for optimizing LNP formulation to control pKa and improve delivery performance.
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