Abstract
The N-terminal domain (163 residues) of Human thrombopoietin (hTPO) is highly conserved and responsible for the receptor-binding. The crystal structure of free hTPO is not yet available, but the crystal structure of its receptor-binding domain (hTPO163) is available in complex with the TN1-Fab antibody. According to a thermodynamic study of hTPO163 binding to TN1-Fab Ab, the ΔH value for binding becomes more negative with an increase in temperature from 283 K to 303 K. The objective of our study is to understand how the free hTPO163 behaves dynamically and to study the effect of temperature on the association of hTPO163 to TN1-Fab antibody through molecular dynamics simulations. We studied the Ag-Ab interactions at two different temperatures 298 K and 303 K. The discontinuous epitope region (residues 98–115) of free hTPO163 displays a conformational switch and it gets stabilized upon binding to the Ab at 303 K. Based on our results, it may be surmised that the epitope region 98–115 is behaving like a disordered epitope. The disordered epitopes are known to be more efficient in binding with the antibody. We also find that, there is an increase in number of hydrogen-bonding interactions and hydrophobic contacts with an increase in the temperature from 298 K to 303 K. Thus, this observation explains a possible reason behind the more negative value of ΔH at the higher temperature 303 K as compared to 298 K.
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