Undergraduate Honors Thesis Projects

Date of Award

2023

Document Type

Honors Paper

Degree Name

Biochemistry and Molecular Biology-BS

Department

Biochemistry and Molecular Biology

Advisor

Dr. John Tansey

First Committee Member

Dr. John Tansey

Second Committee Member

Dr. Jennifer Bennett

Third Committee Member

Dr. Anthony DeStefanis

Keywords

Lipids, Lipid Metabolism, Perilipins, Protein Structure, Protein Function, Protein Docking

Subject Categories

Biochemistry | Higher Education

Abstract

Obesity, type II diabetes mellitus, and non-alcoholic fatty liver disease are all associated with dysfunction of lipid metabolism – the synthesis, storage, and breakdown of lipids. Fats are stored as neutral lipids in the cell and are contained in lipid storage droplets coated with at least one member of the perilipin family of proteins, essential regulators of lipase function. Previous work by Hickenbottom et al. has shown 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. A hydrophobic cleft of unknown function is found at the interface of these two domains. 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 RAPTOR X produces a similar structure that also shows conservation of the pocket of interest. Homology modeling with SWISS-MODEL and use of AlphaFold confirm this as well. The conservation of this cleft suggests that it may have important biological functions. 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 yielded CHEMPLP scores ranging from approximately 25 to 45. Further, a series of fatty acids with varying carbon chain lengths and degrees of unsaturation were docked and yielded high scores ranging from approximately 40 to 82. Increasing CHEMPLP scores correlated with an increase in carbon chain length, and a slight correlation is seen with increasing degrees of unsaturation as well. The highest scores produced in the modeled structure of perilipin 5 were obtained by docking a di- and triglyceride. Docking results were visualized using the molecular visualization software HERMES. The increasing CHEMPLP scores for the molecules examined, and their fits in the pocket, indicate that a hydrophobic metabolite may bind to this pocket, potentially impacting the biological function of this class of proteins. This work may provide a means for the development of small molecules which could be used as possible pharmacological interventions for the treatment of lipid storage disorders.

Licensing Permission

Copyright, all rights reserved. Fair Use

Acknowledgement 1

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Acknowledgement 2

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