Partitioning of Benzoic Acid into 1,2-Dimyristoyl-sn-glycero-3-phosphocholine and Blood-Brain Barrier Mimetic Bilayers.

Abstract:

:Using an all-atom explicit water model and replica exchange umbrella sampling simulations, we investigated the molecular mechanisms of benzoic acid partitioning into two model lipid bilayers. The first was formed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipids, whereas the second was composed of an equimolar mixture of DMPC, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, palmitoylsphingomyelin, and cholesterol to constitute a blood-brain barrier (BBB) mimetic bilayer. Comparative analysis of benzoic acid partitioning into the two bilayers has revealed qualitative similarities. Partitioning into the DMPC and BBB bilayers is thermodynamically favorable although insertion into the former lowers the free energy of benzoic acid by approximately an additional 1 kcal mol-1. The partitioning energetics for the two bilayers is also largely similar based on the balance of benzoic acid interactions with apolar fatty acid tails, polar lipid headgroups, and water. In both bilayers, benzoic acid retains a considerable number of residual water molecules until reaching the bilayer midplane where it experiences nearly complete dehydration. Upon insertion into the bilayers, benzoic acid undergoes several rotations primarily determined by the interactions with the lipid headgroups. Nonetheless, in addition to the depth of the free energy minimum, the BBB bilayer differs from the DMPC counterpart by a much deeper location of the free energy minimum and the appearance of a high free energy barrier and positioning of benzoic acid near the midplane. Furthermore, DMPC and BBB bilayers exhibit different structural responses to benzoic acid insertion. Taken together, the BBB mimetic bilayer is preferable for an accurate description of benzoic acid partitioning.

journal_name

J Chem Inf Model

authors

Siwy CM,Delfing BM,Smith AK,Klimov DK

doi

10.1021/acs.jcim.0c00590

subject

Has Abstract

pub_date

2020-08-24 00:00:00

pages

4030-4046

issue

8

eissn

1549-9596

issn

1549-960X

journal_volume

60

pub_type

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