Trajectories, Structure and Input Files for the MiMiC QM/MM MD Simulation of the R132H Isocitrate Dehydrogenase 1

R132H IDH1 is an important therapeutic target for a variety of brain cancers, yet drug leads and radiotracers which selectively bind only to the mutant over the wild type are so far lacking. Here we have predicted the structural determinants of the Michaelis complex of this mutant using a QM/MM MD-based protocol. It shows some important differences with the X-ray structure, from the metal coordination to the positioning of key residues at the active site. In particular, one lysine residue (K212) emerges as a mostly likely proton donor in the R132H IDH1 catalytic reaction. Intriguingly, the same residue in its deprotonated state is likely to be involved in the reaction catalyzed by the wild-type enzyme (though the mechanisms are different). Our QM/MM protocol could also be used for other metal-based enzymes, which cannot be modelled easily by force field-based MD, like in this case. The attached .zip file contains the following: Coordinates: GROMACS coordinates and trajectory from the QM/MM simulation. Initial: The solvated crystal structure (with hydrogens and counterions) used to start the simulation (.gro format). Both, KH/D and K/DH protomer are given. Final: The coordinates after 20 ps of MiMiC QM/MM MD from the step 3 of the protocol (.gro format). Both, KH/D and K/DH protomer are given. Furthermore for each protomer, each subunit (A and B) was seperately treated in the QM region. This results in 4 coordinate files. Trajectory: The 20 ps MiMiC QM/MM MD trajectory from the step 3 of the protocol (.xtc format). This is sampled at every 0.25 ps with a dt of 0.0005 ps. Both, KH/D and K/DH protomer are given. Furthermore for each protomer, each subunit (A and B) was seperately treated in the QM region. This results in 4 trajectory files. Protocol: Input files and recipe used to run the QM/MM MD simulations of mut-IDH1. Topology: GROMACS topology used for each protomer.