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

This work was supported by Polish National Science Center (NCN) under the Grant No. UMO-2018/29/N/ST4/00507. This research was supported in part by PLGrid Infrastructure (plgsamanta). Preliminary results were obtained during PRACE Summer of HPC programme on ARIS-GRNET.

{"references": ["https://doi.org/10.1021/acs.jcim.1c01157"]}