Discipline: Chemistry and Chemical Sciences
Subcategory: Biochemistry (not Cell and Molecular Biology and Genetics)
Session: 1
Room: Exhibit Hall
Jack DeSalvo - Carthage College
Co-Author(s): Kevin Morris, Carthage CollegeYayin Fang and Matthew George Jr., Howard University
Familial Amyloidal Cardiomyopathy (FAC) is a genetic disease where amyloid fibrils aggregate into plaques around the heart. The disease is caused by the dissociation and aggregation of mutant forms of the transport protein transthyretin (TTR). The TTR mutant studied here had Valine-122 substituted with an Isoleucine. This mutation was chosen due to its presence in 3% of the African American community. In 2019, the compound AG10 entered Phase I clinical trials to treat FAC. AG10 and its derivatives work by stabilizing TTR and preventing disassociation and subsequent plaque formation. Molecular Dynamics (MD) simulations were used to study how the AG10 derivative TKS-14 Tand other similar compounds bind to and stabilize TTR. Our hypothesis was to test the extent to which MD simulations could provide atomic scale insight into the binding of TKS-14 and its derivatives to TTR. These insights could potentially help researchers design new compounds that to stabilize TTR and treat FAC. The software packages AMBER16 (http://ambermd.org/) and MOE (https://www.chemcomp.com/index.htm) were used to carry out all MD simulations and molecular modeling analyses. After the MD simulations were run, we analyzed H-bond formation between the ligands and TTR, as well as the flexibility of the ligands within the TTR binding site.MD simulation analyses showed that TKS-14 binds to TTR by forming H-bonds with Ser-117 residues in the inner TTR binding pocket and interacting with Lys-15 residues near the receptor’s surface. Replacement of the fluorine atom on TKS-14 with other electron donating groups did not impact the molecule’s interaction with TTR. However, when the TKS-14 carboxylate functional group was changed to a tetrazole ring, new hydrogen bond interactions between the ligand and TTR’s Glu-7 residue were recorded. Also, the addition of a carboxylate functional group para- to this tetrazole ring resulted in a novel H-bond interaction between the ligand and TTR residues Thr-106 and Lys-15. These results lead to the conclusion that MD simulation analyses can lead to a better understanding of the intermolecular interactions experienced by TTR stabilizers. Future work will examine structural changes that may facilitate a multi-point stabilizing interaction between ligands and TTR. Free energies of ligand binding for ligand-TTR complexes will also be calculated. 1.Cioffi, C. L., Raja, A., Muthuraman, P., Jayaraman, A., Jayakumar, S., Varadi, A., Petrukhin, K. Journal of Medicinal Chemistry, 2021, 64, 9010–9041. 2.Morris, K. F., Geoghegan, R. M., Palmer, E. E., George, M., & Fang, Y. Biochemistry and Biophysics Reports, 2020, 21, 100721-100732.
Funder Acknowledgement(s): This research was supported by the NSF-REU grant #170934. We also acknowledge the generosity and support of the Ralph E. Klingenmeyer family.
Faculty Advisor: Kevin Morris, kmorris@carthage.edu
Role: I worked to build the protein-ligand intermolecular complexes using MOE, performed and analyzed Molecular dynamics simulations with AMBER16, and interpreted results and designed new studies.