Allosteric Activation of FGFR2 Kinase in Endometrial Cancer: Insights from Gaussian Accelerated Molecular Dynamics and Markov State Model

Abstract

Endometrial carcinoma (EC) is one of the most prevalent gynaecological malignancies found in women. About 10-12% of EC is caused due to mutations in Fibroblast Growth Factor Receptor 2 (FGFR2). It is a tyrosine kinase receptor involved in multiple biological processes like cell proliferation, migration and homeostasis. N549K and K659E mutations of the FGFR2 kinase domain increase the basal kinase activity by 7 to 32-fold. Here, we have considered these mutations along with the wild-type phosphorylated and unphosphorylated FGFR2 kinase to investigate the overall structural dynamics supporting kinase activation in the mutant system.The Gaussian accelerated molecular dynamics (GaMD) approach was utilised to minimise the potential energy barrier during simulation. The results suggest that the mutant systems are more stable than the wild-type ones. The Markov state model (MSM) analysis and Principal component analysis (PCA) highlighted the higher percentage of active-like kinase conformations obtained from mutant systems, which could be a reason behind the higher basal kinase activity. The disengaged molecular brake was believed to be the driving force for mutant kinase activation. The MSM and protein structure network (PSN) analysis have featured the allosteric communication caused by mutation. MSM has shown a secondary structure formation in the ⍺DE loop of the K659E mutant system. PSN and electrostatic interaction reveal that the activating mutations regulate long-range interactions among the αDE loop, αD, αE and αF helices. The pocket made by these regions can act as an allosteric site for inhibitor design. Overall, this study may aid in better therapeutic intervention against endometrial cancer.