(691b) Molecular Simulations of Activating and Inhibitory Protein Interactions in Triglyceride-Rich Lipoprotein Metabolism

Hypertriglyceridemia (HTG) has been strongly linked to cardiovascular disease, hyperchylomicronemia (the inability to correctly break down fats/lipids), and acute pancreatitis. The metabolism of triglyceride-rich lipoproteins (TRLs) has been heavily studied as a result, resulting in identification of many proteins in this pathway, such as lipoprotein lipase (LPL) and its regulators (e.g., the LPL activator apolipoprotein (apo) C-II and the LPL inhibitor angiopoietin-like 4 (ANGPTL4)). Since genetic mutations in LPL—which is the rate-limiting step for removing triglycerides in the bloodstream—are risk factors for HTG, understanding how proteins like apoC-II and ANGPTL4 regulate LPL is of key importance for the development of future therapeutics targeted at LPL.

Herein, we describe the use of molecular dynamics (MD) simulations to investigate the underlying mechanisms of LPL regulation, which remain largely unknown. Specifically, MD simulations were employed to investigate the molecular-level interactions between LPL, apoC-II, and ANGPTL4 and to determine how these interactions are modified in the presence of one another. Our simulations illustrate potential binding mechanisms between these three molecules, which can be confirmed with experiments using synthetic peptides that resemble the binding residues of ANGPTL4 and apoC-II. Qualitative trends are drawn between the activating and inhibitory mechanisms of the LPL-bound proteins, which can be applied to other regulators, like apoC-I or GP1HBP1, that work to stabilize or disrupt LPL in its metabolism of TRL. Ultimately, insights from these simulations may serve to guide the design of novel pharmaceuticals for treating or preventing HTG-related diseases.