Theoretical Assessment of Fluorinated Phospholipids in the Design of Liposomal Drug-Delivery Systems

Abstract

Fluorinated phospholipid analogues are investigated as potential substrates for phospholipase A2 (PLA2) using classical molecular dynamics simulations and quantum mechanics/density functional theory calculations. The fluorinated phospholipid analogues are α-fluoro (HF-ProAEL) and α,α-difluoro (F2-ProAEL) conjugates of (R)-1-O-hexadecyl-2-palmitoyl-sn-glycero-3-phoshocholineglycerol (ProAEL). Our results provide a theoretical assessment of the potential usefulness of these fluorinated lipids in the rational design of liposomal drug-delivery systems. The α-fluorine-substituted phospholipid analogues are found to be substrates for secretory PLA2, with sufficient accessibility of water to the active site to allow for enzymatic hydrolysis. Because of the inherently less stable nature of HF-ProAEL and F2-ProAEL when compared to that of ProAEL, the hydrolytic reaction is predicted to occur at a progressively faster rate; the more electronegative substituent at the α-position effectively lowers the energy barrier for hydrolysis. We conclude that the partially fluorinated phospholipid analogues facilitate rational design of liposomal vesicles of phospholipid mixtures with desirable physicochemical properties and that are still subjects for important and pharmaceutically proven drug-delivery mechanisms.

Water-Intake and Water-Molecule Paths to the Active Site of Secretory Phospholipase A2 Studied Using MD Simulations and the Tracking Tool AQUA-DUCT

“…Determining the energy barrier along the reaction coordinate requires QM/MM calculations, as has previously been performed on sPLA 2 -IIA−substrate complexes. 42,60 Role of Phe 5 and Tyr 51 . From the multiple sequence alignment of 97 different sPLA 2 sequences, it is seen that His 47 , Asp 48 , Tyr 51 , and Asp 91 are highly conserved residues.…”

“…However, monitoring the distances between key residues in the Michaelis–Menten complex does not provide information about the energy barrier of the enzymatic reaction along the reaction coordinate and can, therefore, not stand alone in the search for possible substrates. Determining the energy barrier along the reaction coordinate requires QM/MM calculations, as has previously been performed on sPLA 2 -IIA–substrate complexes. , …”