Discovery of a new binding site and a possible gain in neomorphic activity in R132H_IDH1

, the IDH1-apo form and the ICT, NADPH, and ICT_NADPH-bound complexes, with the monomer subunit of the mutated (R132H_IDH1) as well as the wild-type IDH1, under atomistic force fields. In this work, we report that the R132H mutation enhances flexibility, triggering disorder in various functionally relevant subdomains compared to their wild-type counterparts, which can subsequently redistributes the conformational space of IDH1. Accordingly, the disorderliness of the regulatory segments and the disruption of the hydrogen-bonding network in the vicinity of the mutant site result in a loss of binding affinity of ICT_NADPH at the active site, thereby altering normal catalytic activity. Clustering of principal components using unsupervised machine learning (ML) methods uncovers distinct, thermodynamically stable conformations for mutant and wild-type IDH1. These findings support the earlier reported experimental studies. Nevertheless, the comprehensive analysis of the simulated trajectory of ICT_NADPH-bound R132H_IDH1 reveals a non-canonical interaction region that is dynamically accessible to ICT/NADPH, which is probably responsible for the gain in the neomorphic activity that has not been previously detected or reported. Hence, we strongly believe that these findings may lead to therapeutic advances in the treatment of glioma.