Comparative MD analysis of the stability of transthyretin providing insight into the fibrillation mechanism.
Proteins can misfold and aggregate, which is believed to be the cause of a variety of diseases, affecting very diverse organs in the body. Many questions about the nature of aggregation and the proteins that are involved in these events are still left unanswered. One of the proteins that is known to form amyloids is transthyretin (TTR), the secondary transporter of thyroxine, and transporter of retinol-binding protein. Several experimental results have helped to explain this aberrant behavior of TTR; however, structural insights of the amyloidgenic process are still lacking. Therefore, we have used all-atom MD simulation and free energy calculations to study the initial phase of this process. We have calculated the free energy changes of the initial tetramer dissociation under different conditions and in the presence of thyroxine. We show that tetramer formation is indeed only thermodynamically favorable in neutral pH conditions. We find that binding of two thyroxine molecules stabilizes the complex, and that this occurs with negative cooperativity. In addition to the energetic calculations, we have also investigated the dominant motions of the TTR and found that only the dimeric form of the protein could undergo the initial fibril formation.
Sørensen
Jesper
J
Department of Chemistry, Aarhus University, Aarhus C, 8000, Denmark.
Hamelberg
Donald
D
Schiøtt
Birgit
B
McCammon
J Andrew
JA
D018360:Crystallography, X-Ray; D004734:Energy Metabolism; D019277:Entropy; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics; D011487:Protein Conformation; D017510:Protein Folding; D013816:Thermodynamics; D013974:Thyroxine / Q000737:chemistry
D008024:Ligands; D011228:Prealbumin; D013974:Thyroxine