Analysis of the Hydrophobic Cleft of Perilipins 3 and 5.

Obesity, type II diabetes mellitus, and non-alcoholic fatty liver disease are all diseases associated with dysfunction of lipid metabolism or lipid mobilization - the breakdown of lipids into free fatty acids and glycerol. Because of this, research done on topics related to lipid metabolism provides potentially valuable insight into disease pathogenesis. Neutral lipids in the cell are stored in lipid storage droplets coated with at least one of the perilipin family of proteins, essential regulators of lipase function. Previous work by other laboratories has indicated that the carboxy terminus of perilipin 3 folds into a boot-like structure consisting of a four-helix bundle capped by a mixed α-β domain. At the interface of the four-helix bundle and the mixed α-β domain is a hydrophobic cleft of unknown function. The genomic organization, nucleotide sequence, and amino acid sequence of perilipins 3 and 5 are highly conserved, particularly in the region that contains this hydrophobic cleft. Threading the sequence of perilipin 5 onto perilipin 3 using both RAPTOR X and PHYRE 2 produces a similar structure that also includes conservation of the pocket of interest. To study interactions of the hydrophobic pocket, models of the proteins were docked in silico to a series of small organic biological molecules using the GOLD software package from Cambridge Crystallographic Database. Mono and bicyclic systems were docked and yielded CHEMPLP scores ranging from approximately 25 to 45. Docking results were visualized and verified and fits compared using the molecular visualization software HERMES. Examination of current results informed future decisions of which candidate molecules to attempt to dock. The increasing CHEMPLP scores for the molecules examined, and their fits into the pocket seen in Hermes, indicate that a small molecule may bind to this pocket, potentially impacting the biological function of this class of proteins. Additionally, this work may provide a means for development of small molecules which could be used as possible pharmacological interventions for the treatment of lipid storage disorders.