Discipline: Chemistry and Chemical Sciences
Subcategory: Biochemistry (not Cell and Molecular Biology and Genetics)
Room: Exhibit Hall A
Allison Wesel - Carthage College
Co-Author(s): Riley Geoghegan, Carthage College, Kenosha, WI; Emily Parker, Carthage College, Kenosha, WI; Kevin Morris, Carthage College, Kenosha, WI; Matthew George Jr., Howard University College of Medicine, Washington DC; Yayin Fang, Howard University College of Medicine, Washington DC .
Familial Amyloidal Cardiomyopathy is a disease in which amyloid fibrils aggregate into plaques in the heart. It is caused by the dissociation, misfolding, and aggregation of wild type and mutated forms of the protein Transthyretin (TTR). TTR is a transport protein produced in the liver. The TTR mutants studied here had Valine-122 substituted with an Isoleucine (V122I) or Valine-30 substituted with a Methionine (V30M). The former mutation is present in 3% of the African American population. Molecular dynamics (MD) simulations were used to study how the drug candidate AG10, its decarboxy derivative, and two natural products (alpha- and gamma-mangostin) associated with the V122I and V30M TTR mutants. All these compounds have been shown experimentally to bind to TTR and inhibit its aggregation into plaques. The hypothesis of our work was that MD simulations could provide atomic scale insight into the intermolecular interactions responsible for drug binding to TTR. These insights in turn could potentially help researchers identify other target compounds that may also stabilize the TTR protein. The software packages AMBER 16 (ambermd.org/) and MOE (Molecular Operating Environment, www.chemcomp.com) were used to carry out all MD simulation and molecular modeling experiments. After the MD simulations were run, we analyzed hydrogen bond formation, inter-atom distances, and solvent accessible surface areas. Structures were also superimposed to study changes in the ligands? conformations within the TTR binding pocket. Free energies of ligand binding were calculated as well. Analysis of the AG10: V122I results showed that the ligand experienced stable, two-point interactions with the protein by forming hydrogen bonds with Ser-117 residues in the inner TTR binding pocket and Lysine-15 residues near the surface of the receptor. Removal of the AG10 carboxylate functional group disrupted this two-point interaction, causing the ligand to undergo a conformational change within the TTR binding site. In contrast, the alpha- and gamma-mangostin ligands bound to the V30M mutant primarily through hydrophobic interactions with receptor residues Ala-108, Leu-110, Ser-117, and Thr-119. Therefore, we can conclude that hydrogen bonding and hydrophobic interactions both play important roles in governing ligand binding to TTR mutants. Future work will use MD simulations to develop more detailed models of AG10, alpha- and gamma-mangostin binding to TTR. Systematic changes will also be made to the alpha- and gamma-mangostin functional groups to identify the ones that play the greatest role in TTR binding. References: Yokoyama, T., et al. Discovery of Gamma-Mangostin as an Amyloidogenesis Inhibitor. Scientific Reports, 5, 13570-13579. Penchala, S.C., et al. AG10 Inhibits Amyloidogenesis and Cellular Toxicity of the Familial Amyloid Cardiomyopathy-Associated V122I Transthyretin, PNAS, 110(24), 9992-9997.
Funder Acknowledgement(s): NIH grant (#G12 MD007579) to the RCMI program at Howard University; HUMAA Endowed Founder?s Chair in Basic Science award to Dr. Yayin Fang; NSF-RUI grant (#1709394) to Carthage College; We also acknowledge the generosity of the Ralph E. Klingenmeyer family
Faculty Advisor: Kevin Morris, email@example.com
Role: My portion of this project used AMBER 16 and MOE software to study the binding of magnostin ligands to the V30M transthyretin variant. In particular, I studied the hydrophobic pocket that formed inside the TTR protein and how the magnostin ligands interacted within that pocket. I then compared my results to work done by other researchers in our lab with the AG10 ligand. My overall goal was to understand how hydrophobic interactions help govern the binding of magnostin ligands to the V30M transthyretin protein.