Why GPCRs behave differently in cubic and lamellar lipidic mesophases

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• 作者：George Khelashvili ; Pedro Blecua Carrillo Albornoz ; Niklaus Johner ; Sayan Mondal ; Martin Caffrey ; Harel Weinstein
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：September 26, 2012
• 年：2012
• 卷：134
• 期：38
• 页码：15858-15868
• 全文大小：678K
• 年卷期：v.134,no.38(September 26, 2012)
• ISSN：1520-5126

文摘

Recent successes in the crystallographic determination of structures of transmembrane proteins in the G protein-coupled receptor (GPCR) family have established the lipidic cubic phase (LCP) environment as the medium of choice for growing structure-grade crystals by the method termed 鈥渋n meso鈥? The understanding of in meso crystallogenesis is currently at a descriptive level. To enable an eventual quantitative, energy-based description of the nucleation and crystallization mechanism, we have examined the properties of the lipidic cubic phase system and the dynamics of the GPCR rhodopsin reconstituted into the LCP with coarse-grained molecular dynamics simulations with the Martini force-field. Quantifying the differences in the hydrophobic/hydrophilic exposure of the GPCR to lipids in the cubic and lamellar phases, we found that the highly curved geometry of the cubic phase provides more efficient shielding of the protein from unfavorable hydrophobic exposure, which leads to a lesser hydrophobic mismatch and less unfavorable hydrophobic鈥揾ydrophilic interactions between the protein and lipid鈥搘ater interface in the LCP, compared to the lamellar phase. Since hydrophobic mismatch is considered a driving force for oligomerization, the differences in exposure mismatch energies between the LCP and the lamellar structures suggest that the latter provide a more favorable setting in which GPCRs can oligomerize as a prelude to nucleation and crystal growth. These new findings lay the foundation for future investigations of in meso crystallization mechanisms related to the transition from the LCP to the lamellar phase and studies aimed at an improved rational approach for generating structure-quality crystals of membrane proteins.