Molecular dynamics simulation study of AG10 and tafamidis binding to the Val122Ile transthyretin variant
Molecular dynamics (MD) simulations were used to investigate the binding of four ligands to the Val122Ile mutant of the protein transthyretin. Dissociation, misfolding, and subsequent aggregation of mutated transthyretin proteins are associated with the disease Familial Amyloidal Cardiomyopathy. The...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-03-01
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| Series: | Biochemistry and Biophysics Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405580819302110 |
| _version_ | 1828384112885366784 |
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| author | Kevin F. Morris Riley M. Geoghegan Emily E. Palmer Matthew George, Jr. Yayin Fang |
| author_facet | Kevin F. Morris Riley M. Geoghegan Emily E. Palmer Matthew George, Jr. Yayin Fang |
| author_sort | Kevin F. Morris |
| collection | DOAJ |
| description | Molecular dynamics (MD) simulations were used to investigate the binding of four ligands to the Val122Ile mutant of the protein transthyretin. Dissociation, misfolding, and subsequent aggregation of mutated transthyretin proteins are associated with the disease Familial Amyloidal Cardiomyopathy. The ligands investigated were the drug candidate AG10 and its decarboxy and N-methyl derivatives along with the drug tafamidis. These ligands bound to the receptor in two halogen binding pockets (HBP) designated AB and A’B’. Inter-ligand distances, solvent accessible surface areas, root mean squared deviation measurements, and extracted structures showed very little change in the AG10 ligands' conformations or locations within the HBP during the MD simulation. In addition, the AG10 ligands experienced stable, two-point interactions with the protein by forming hydrogen bonds with Ser-117 residues in both the AB and A’B’ binding pockets and Lysine-15 residues found near the surface of the receptor. Distance measurements showed these H-bonds formed simultaneously during the MD simulation. Removal of the AG10 carboxylate functional group to form decarboxy-AG10 disrupted this two-point interaction causing the ligand in the AB pocket to undergo a conformational change during the MD simulation. Likewise, addition of a methyl group to the AG10 hydrazone functional group also disrupted the two-point interaction by decreasing hydrogen bonding interactions with the receptor. Finally, MD simulations showed that the tafamidis ligands experienced fewer hydrogen bonding interactions than AG10 with the protein receptor. The tafamidis ligand in pocket A’B’ was also found to move deeper into the HBP during the MD simulation. Keywords: Molecular dynamics simulation, Transthyretin, Tafamidis, AG10, Val122Ile mutant |
| first_indexed | 2024-12-10T04:59:20Z |
| format | Article |
| id | doaj.art-5791165ec5aa460f801c25f75b37ee4a |
| institution | Directory Open Access Journal |
| issn | 2405-5808 |
| language | English |
| last_indexed | 2024-12-10T04:59:20Z |
| publishDate | 2020-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biochemistry and Biophysics Reports |
| spelling | doaj.art-5791165ec5aa460f801c25f75b37ee4a2022-12-22T02:01:26ZengElsevierBiochemistry and Biophysics Reports2405-58082020-03-0121Molecular dynamics simulation study of AG10 and tafamidis binding to the Val122Ile transthyretin variantKevin F. Morris0Riley M. Geoghegan1Emily E. Palmer2Matthew George, Jr.3Yayin Fang4Department of Chemistry, Carthage College, 2001 Alford Park Drive, Kenosha, WI, 53140, USADepartment of Chemistry, Carthage College, 2001 Alford Park Drive, Kenosha, WI, 53140, USADepartment of Chemistry, Carthage College, 2001 Alford Park Drive, Kenosha, WI, 53140, USADepartment of Biochemistry and Molecular Biology, Howard University College of Medicine, Howard University, 520 W Street NW, Washington, DC, 20059, USADepartment of Biochemistry and Molecular Biology, Howard University College of Medicine, Howard University, 520 W Street NW, Washington, DC, 20059, USA; Corresponding author.Molecular dynamics (MD) simulations were used to investigate the binding of four ligands to the Val122Ile mutant of the protein transthyretin. Dissociation, misfolding, and subsequent aggregation of mutated transthyretin proteins are associated with the disease Familial Amyloidal Cardiomyopathy. The ligands investigated were the drug candidate AG10 and its decarboxy and N-methyl derivatives along with the drug tafamidis. These ligands bound to the receptor in two halogen binding pockets (HBP) designated AB and A’B’. Inter-ligand distances, solvent accessible surface areas, root mean squared deviation measurements, and extracted structures showed very little change in the AG10 ligands' conformations or locations within the HBP during the MD simulation. In addition, the AG10 ligands experienced stable, two-point interactions with the protein by forming hydrogen bonds with Ser-117 residues in both the AB and A’B’ binding pockets and Lysine-15 residues found near the surface of the receptor. Distance measurements showed these H-bonds formed simultaneously during the MD simulation. Removal of the AG10 carboxylate functional group to form decarboxy-AG10 disrupted this two-point interaction causing the ligand in the AB pocket to undergo a conformational change during the MD simulation. Likewise, addition of a methyl group to the AG10 hydrazone functional group also disrupted the two-point interaction by decreasing hydrogen bonding interactions with the receptor. Finally, MD simulations showed that the tafamidis ligands experienced fewer hydrogen bonding interactions than AG10 with the protein receptor. The tafamidis ligand in pocket A’B’ was also found to move deeper into the HBP during the MD simulation. Keywords: Molecular dynamics simulation, Transthyretin, Tafamidis, AG10, Val122Ile mutanthttp://www.sciencedirect.com/science/article/pii/S2405580819302110 |
| spellingShingle | Kevin F. Morris Riley M. Geoghegan Emily E. Palmer Matthew George, Jr. Yayin Fang Molecular dynamics simulation study of AG10 and tafamidis binding to the Val122Ile transthyretin variant Biochemistry and Biophysics Reports |
| title | Molecular dynamics simulation study of AG10 and tafamidis binding to the Val122Ile transthyretin variant |
| title_full | Molecular dynamics simulation study of AG10 and tafamidis binding to the Val122Ile transthyretin variant |
| title_fullStr | Molecular dynamics simulation study of AG10 and tafamidis binding to the Val122Ile transthyretin variant |
| title_full_unstemmed | Molecular dynamics simulation study of AG10 and tafamidis binding to the Val122Ile transthyretin variant |
| title_short | Molecular dynamics simulation study of AG10 and tafamidis binding to the Val122Ile transthyretin variant |
| title_sort | molecular dynamics simulation study of ag10 and tafamidis binding to the val122ile transthyretin variant |
| url | http://www.sciencedirect.com/science/article/pii/S2405580819302110 |
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