Inactive to active transition of human Thymidine Kinase 1 revealed by Molecular Dynamics simulations

The trajectories and input files for the manuscript <em>Inactive to active transition of human Thymidine</em> <em>Kinase 1 revealed by Molecular Dynamics simulations</em> (https://doi.org/10.1021/acs.jcim.1c01157) ABSTRACT Despite its importance for the nucleoside (and nucleoside prodrug) metabolism, the structure<br> of the active conformation of human Thymidine Kinase 1 (hTK1) remains elusive. We perform<br> microsecond molecular dynamics simulations of the inactive enzyme form bound to a<br> bisubstrate inhibitor that was shown experimentally to activate another TK1-like kinase,<br> Thermotoga maritima TK (TmTK). Our results are in excellent agreement with the<br> experimental findings for the TmTK closed-to-open state transition. We show that the inhibitor<br> induces an increase of the enzyme radius of gyration due to the expansion on one of the dimer<br> interfaces; the structural changes observed, including the active site pocket volume increase,<br> decrease in monomer-monomer buried surface area and of the number of hydrogen bonds (as<br> compared to the inactive enzyme control simulation), show that the catalytically competent<br> (open) conformation of hTK1 can be assumed in the presence of an activating ligand.