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. 2006 Mar 28;103(13):4888-93.
doi: 10.1073/pnas.0508352103. Epub 2006 Mar 17.

A Role for Direct Interactions in the Modulation of Rhodopsin by omega-3 Polyunsaturated Lipids

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Free PMC article

A Role for Direct Interactions in the Modulation of Rhodopsin by omega-3 Polyunsaturated Lipids

Alan Grossfield et al. Proc Natl Acad Sci U S A. .
Free PMC article

Abstract

Rhodopsin, the G protein-coupled receptor primarily responsible for sensing light, is found in an environment rich in polyunsaturated lipid chains and cholesterol. Biophysical experiments have shown that lipid unsaturation and cholesterol both have significant effects on rhodopsin's stability and function; omega-3 polyunsaturated chains, such as docosahexaenoic acid (DHA), destabilize rhodopsin and enhance the kinetics of the photocycle, whereas cholesterol has the opposite effect. Here, we use molecular dynamics simulations to investigate the possibility that polyunsaturated chains modulate rhodopsin stability and kinetics via specific direct interactions. By analyzing the results of 26 independent 100-ns simulations of dark-adapted rhodopsin, we found that DHA routinely forms tight associations with the protein in a small number of specific locations qualitatively different from the nonspecific interactions made by saturated chains and cholesterol. Furthermore, the presence of tightly packed DHA molecules tends to weaken the interhelical packing. These results are consistent with recent NMR work, which proposes that rhodopsin binds DHA, and they suggest a molecular rationale for DHA's effects on rhodopsin stability and kinetics.

Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.
Packing scores for membrane components. (A) The normalized probability distributions for the packing scores of DHA, STEA, and cholesterol. The error bars are the SD of the averages computed for the 26 independent trajectories and, as such, represent the uncertainty for the probability computed with a 100-ns simulation. Approximately 70% of the lipids have packing scores between 0 and 0.1. (B) The relative probability for the protein to make a given packing score with each membrane component, computed by taking the data from A and rescaling according to the relative abundance of DHA, STEA, and cholesterol molecules in the system.
Fig. 2.
Fig. 2.
Fraction of lipid chains with a given score, summed over all lipids in all trajectories. Scores of >0.6 are merged into a single bin to improve statistics.
Fig. 3.
Fig. 3.
Groups of residues that tightly associate with membrane components, projected onto the 1U19 crystal structure. Upper and Lower are views with helices 6 and 4 in front, respectively. (Left) The residues that interact with DHA are highlighted. (Center) The residues that interact with STEA are highlighted. (Right) The residues that interact with cholesterol are highlighted. Different colors indicate the distinct groups defined in Tables 1–3. The “binding sites” for different membrane components overlap in places, most notably between helices 6 and 7 (upper left part of the protein) (Upper) and between helices 3 and 4 (bottom center of the protein) (Lower).
Fig. 4.
Fig. 4.
Groups of residues that preferentially interact with DHA, STEA, or cholesterol projected onto the 1U19 crystal structure. The average packing score between each residue and each membrane component was computed across all simulations. Residues are colored blue if the DHA score is significantly higher than that for STEA and cholesterol. Residues for which the STEA score is significantly higher are shown in red. Magenta residues have significantly higher cholesterol scores. Green residues have either no significant preference or very weak overall signals. In all cases, significance was determined by comparing the difference between the two values with the sum of the standard errors in those values.
Fig. 5.
Fig. 5.
Comparison of residue–residue packing scores from trajectories with and without lipids bound to those sites. We computed normalized histograms for the packing scores for interhelix residue pairs found in the groups from Table 1 (see text for details). (A) The probability distributions. (B) Ratio of the probability distributions.

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