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.