Abstract
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 key proton-transfer step of 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.