Docosahexaenoic acid alters bilayer elastic properties

*Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021; and
^†Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701

Edited by Alexander Leaf, Harvard University, Charlestown, MA, and approved April 24, 2007 (received for review February 2, 2007)

Abstract

At low micromolar concentrations, polyunsaturated fatty acids (PUFAs) alter the function of many membrane proteins. PUFAs exert their effects on unrelated proteins at similar concentrations, suggesting a common mode of action. Because lipid bilayers serve as the common “solvent” for membrane proteins, the common mechanism could be that PUFAs adsorb to the bilayer/solution interface to promote a negative-going change in lipid intrinsic curvature and, like other reversibly adsorbing amphiphiles, increase bilayer elasticity. PUFA adsorption thus would alter the bilayer deformation energy associated with protein conformational changes involving the protein/bilayer boundary, which would alter protein function. To explore the feasibility of such a mechanism, we used gramicidin (gA) analogues of different lengths together with bilayers of different thicknesses to assess whether docosahexaenoic acid (DHA) could exert its effects through a bilayer-mediated mechanism. Indeed, DHA increases gA channel appearance rates and lifetimes and decreases the free energy of channel formation. The appearance rate and lifetime changes increase with increasing channel-bilayer hydrophobic mismatch and are not related to differing DHA bilayer absorption coefficients. DHA thus alters bilayer elastic properties, not just lipid intrinsic curvature; the elasticity changes are important for DHA's bilayer-modifying actions. Oleic acid (OA), which has little effect on membrane protein function, exerts no such effects despite OA's adsorption coefficient being an order of magnitude greater than DHA's. These results suggest that DHA (and other PUFAs) may modulate membrane protein function by bilayer-mediated mechanisms that do not involve specific protein binding but rather changes in bilayer material properties.

Footnotes

^‡To whom correspondence should be addressed. E-mail: sparre{at}med.cornell.edu
Author contributions: M.J.B. and O.S.A. designed research; R.E.K. and O.S.A. designed the gramicidin analogues; M.J.B. performed research; M.J.B. analyzed data; and M.J.B., R.E.K., and O.S.A. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0701015104/DC1.
↵ § FAs absorb to surfaces, and the nominal FA concentrations (based on the total amount added) are higher than the actual concentrations (see Discussion).
Abbreviations:

PUFA,

polyunsaturated fatty acid;

OA,

oleic acid;

gA,

gramicidin;

DHA,

docosahexaenoic acid.