Molecular dynamics simulation of a human thiopurine S-methyltransferase complexed with 6-mercaptopurine model

Human thiopurine S-methyltransferase (TPMT) is an essential protein in 6-mercaptopurine (6MP) drug metabolism. To understand the pharmacogenetics of TPMT and 6MP, X-ray co-crystal structures of TPMT complexes with S-adenosyl-L-methionine (AdoMet) and 6MP are required. However, the co-crystal structure of this complex has not been reported because 6MP is poorly water soluble. We used molecular dynamics (MD) simulation to predict the structure of the complex of human TPMT-AdoHcy(CH₂)6MP, where the sulfur atoms of AdoHcy and 6MP were linked by a CH₂ group. After 1300 picoseconds of MD simulation, the trajectory showed that 6MP was stabilized in the TPMT active site by formation of non-bonded interactions between 6MP and Phe40, Pro196 and Arg226 side chains of TPMT. The intersulfur distance between AdoHcy and 6MP as well as the binding modes and the interactions of our TPMT-AdoHcy model are consistent with those observed in the X-ray crystal structure of murine TPMT-AdoHcy-6MP complex. The predicted binding modes of AdoHcy and 6MP in our model are consistent with those observed in murine TPMT X-ray crystal structures, which provides structural insights into the interactions of TPMT, AdoHcy, and 6MP at the atomic level and may be used as a starting point for further study of thiopurine drug pharmacogenetics.