Polyunsaturated fatty acids are known to dramatically change the structural and dynamic properties of membrane bilayers, and to modulate the properties of membrane proteins, most notably the GPCR Rhodopsin that resides in rod outer cell membranes greatly enriched in docosahexaenoic acid (DHA). We previously showed that DHA exhibits unique lipid-protein interactions with Rhodopsin and hypothesized that increased DHA-Rhodopsin contacts come at the expense of helix-helix interactions in the protein. This model explains the experimentally observed lowering of Rhodopsin's unfolding temperature with increasing polyunsaturation and suggests a novel mechanism by which DHA lowers the energy of activation to the light adapted state by destabilizing the ground state. To further test this idea we have constructed MD simulations of model transmembrane helices in lipid bilayers composed of saturated dipalmitoylphosphatidylcholine (DPPC) and of polyunsaturated 1-palmitoyl-2-docosahexaenoylphosphatidylcholine (PDPC), lipids chosen based on their essentially identical hydrophobic thickness. For each lipid we have computed the potential of mean force as a function of helix-helix distance. To address the substantial sampling challenges posed by slow relaxation of peptide and lipid conformations we employed replica exchange umbrella sampling after generating independent lipid starting configurations for each window. Using thermodynamic integration, with mean forces averaged over greater than one microsecond of simulation, we found a significant difference for the dimerization energy of the two lipids. The helix-helix association energy is greatly diminished in the DHA containing membrane, consistent with our stated hypothesis. By decomposing the mean force into contributions from helix-helix and membrane-helix interactions we found that DHA disrupts attractive interactions between the helices. These results highlight the importance of the lipid bilayer, and in particular short-range direct lipid-protein interactions, in modulating the structure and function of membrane proteins.