Dynamic Mechanism for the carriage and release of thyroxine in the blood, a molecular dynamic study

Salta

Congreso; XXXIX Annual Meeting of Argentinena Biophysical Society SAB 2010, 3rd Latin American Protein Society; 2010

p { margin-bottom: 0.21cm; } Thyroid hormones are carried in the blood by serum proteins. The mayor fraction of T4 (75%) is bound to T4-binding globulin (TBG). This non-inhibitory member of the serpin family of the serine proteinase inhibitors shows, as one of the main significant structural elements, the reactive center loop (RCL). The RCL is susceptible to proteolytic cleavage by the elastases and other proteases released in inflammatory sites.Cleavage of the loop results in the conformational change that typifies serpins, consisting in the transition from a stressed S state to relaxed R state. This S-to-R change is associated with an increase in the protein thermo stability and a small decrease in the ligand binding affinity.1 On the other hand, thyroxine-binding site of the cleaved T4-TBG complex (T4-cTBG) and cleaved TBG (cTBG) crystal structure adopts a configuration that resebles that of the native T4-TBG complex.2 In order to bring light on the understanding about the mechanism involved in the S-to-R transition, we perfromed molecular dynamic simulations on the following systems: T4-TBG, TBG, T4-cTBG and cTBG. Subsequent molecular mechanics Poisson-Boltzmann surface areas and essentials models were calculated together with a detailed structural analysis for each system. We do not find significant differences among the dynamics of the respective binding sites in T4-TBG, TBG and T4-cTBG. However, a change in the H bond network in the cTBG system was found, that could explain the small difference between the binding affinities of the two, S and R, states. 1 – Janssen OE, Golcher HMB, Grasnerger H, Saller B, Mann K, Refetoff S, J Clin End Metab (2002), 87:1217-1222 2 – Zhou A, Wei Z, Read RJ, Carrell RW, PNAS (2006), 103:13321-13326