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On the Structure and Flip-flop of Free Docosahexaenoic Acid in a Model Human Brain Membrane

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Pages (from-to)8038-8047
Number of pages10
JournalThe journal of physical chemistry. B
Issue number29
Early online date16 Jun 2021
E-pub ahead of print16 Jun 2021
Published29 Jul 2021

Bibliographical note

Funding Information: The authors are grateful for the computational support provided by the UK’s HEC Materials Chemistry Consortium (funded by the EPSRC EP/L000202, EP/R029431, EP/T022213) that has allowed us to use the ARCHER UK National Supercomputing Service ( ) and the UK Materials and Molecular Modelling Hub, which is partially funded by the EPSRC for THOMAS (EP/P020194) and for YOUNG (EP/T022213) to carry out the MD simulations reported in this manuscript. Publisher Copyright: © 2021 American Chemical Society.


King's Authors


Among the omega-3 fatty acids, docosahexaenoic acid (DHA, sn22:6) is particularly vital in human brain cell membranes. There is considerable interest in DHA because low-level DHA has been associated with declined cognitive function and poor visual acuity. In this work, atomistic molecular dynamics simulations were used to investigate the effects of free protonated DHA (DHAP) in molar fractions of 0, 17, 30, and 38% in a realistic model of a healthy brain cell membrane comprising 26 lipid types. Numerous flip-flop events of DHAP were observed and categorized as successful or aborted. Novel use of the machine learning technique, density-based spatial clustering of applications with noise (DBSCAN), effectively identified flip-flop events by way of clustering. Our data show that increasing amounts of DHAP in the membrane disorder the bilayer packing, fluidize the membrane, and increase the rates of successful flip-flop from k = 0.2 μs–1 (17% DHAP) to 0.8 μs–1 (30% DHAP) and to 1.3 μs–1 (38% DHAP). In addition, we also provided a detailed understanding of the flip-flop mechanism of DHAP across this complex membrane. Interestingly, we noted the role of hydrogen bonds in two distinct coordinated flip-flop phenomena between two DHAP molecules: double flip-flop and assisted flip-flop. Understanding the effects of various concentrations of DHAP on the dynamics within a lipid membrane and the resulting structural properties of the membrane are important when considering the use of DHAP as a dietary supplement or as a potential therapeutic.

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