Decoupling the dynamic mechanism revealed by FGFR2 mutation-induced population shift

Abstract

The fibroblast growth factor receptor 2 (FGFR2) is a key component in cellular signaling networks, and its dysfunctional activation has been implicated in various diseases including cancer and developmental disorders. Mutations at the activation loop (A-loop) have been suggested to trigger an increased basal kinase activity. However, the molecular mechanism underlying this highly dynamic process has not been fully understood due to the limitation of static structural information. Here, we conducted multiple, large-scale Gaussian accelerated molecular dynamics simulations of five (K659E, K659N, K659M, K659Q, and K659T) FGFR2 mutants at the A-loop, and comprehensively analyzed the dynamic molecular basis of FGFR2 activation. The results quantified the population shift of each system, revealing that all mutants had a higher proportion of active-like states. Using Markov state models, we extracted the representative structure of different conformational states and identified key residues related to the increased kinase activity. Furthermore, community network analysis showed enhanced information connections in the mutants, highlighting the long-range allosteric communication between the A-loop and the hinge region. Our findings may provide insights into the dynamic mechanism for FGFR2 dysfunctional activation and allosteric drug discovery. Communicated by Ramaswamy H. Sarma