Trollmann M, Rossetti P, Böckmann R (2026)
Publication Type: Journal article
Publication year: 2026
Book Volume: 125
Pages Range: 3918-3937
Journal Issue: 15
DOI: 10.1016/j.bpj.2026.06.030
Ionizable aminolipids enable lipid nanoparticles (LNPs) to encapsulate nucleic acids at neutral pH and to release their cargo upon endosomal acidification. The discrepancy between this effective, acidic LNP pKa and the basic intrinsic pKa of aminolipids, however, remains poorly understood. Here, we performed microsecond constant-pH molecular dynamics simulations of five widely used aminolipids (DODAP, DLin-MC3-DMA, DLin-KC2-DMA, ALC-0315, and SM-102) embedded in different LNP-relevant ternary DOPC/DSPC-cholesterol membranes to quantify how aminolipid structure and membrane composition jointly govern aminolipid protonation and the associated pH-dependent membrane remodeling. Across all systems, membrane embedding lowers the apparent aminolipid pKa, yielding physiologically relevant values of 6-7.5 corresponding to shifts by up to 3.5 pKa units or approx. 20 kJ mol-1 with respect to the intrinsic pKa. Strikingly, pH-driven membrane remodeling upon deprotonation differs between aminolipids: polyunsaturated aminolipids undergo surface-to-core translocation, branched aminolipids preferentially form laterally segregated surface domains, and DODAP remains interfacially anchored through sustained hydration and hydrogen bonding. Saturated helper lipids (DSPC) systematically enhance segregation and amplify pKa shifts relative to DOPC. Together, these results identify membrane phase behavior as a primary regulator of aminolipid protonation equilibria and provide insights into how formulation may influence LNP pKa and thereby could control membrane remodeling and delivery performance.
APA:
Trollmann, M., Rossetti, P., & Böckmann, R. (2026). Membrane environment sets the functional pKa of ionizable lipids. Biophysical Journal, 125(15), 3918-3937. https://doi.org/10.1016/j.bpj.2026.06.030
MLA:
Trollmann, Marius, Paolo Rossetti, and Rainer Böckmann. "Membrane environment sets the functional pKa of ionizable lipids." Biophysical Journal 125.15 (2026): 3918-3937.
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