Exploring the Profiles of ROS1 Tyrosine Kinase: A Structural Analysis of G2032R and D2033N Mutations.

Abstract

Background: ROS1, a proto-oncogene, drives cancer through chromosomal fusions. The G2032R and D2033N mutations, common in ROS1-rearranged non-small cell lung cancer, hinder crizotinib treatment. We investigate these mutations' impact on ROS1 structure through molecular dynamics (MD) simulations, revealing destabilization. Our findings shed light on how these mutations contribute to cancer development.

Materials and methods: The crystal structure of human ROS1 (PDB ID: 7z5x) served as the template for homology modeling and further mutation insertion of G2032R and D2033N substitutions introduced using Swiss-PdbViewer. The MD simulations were conducted on the wild-type (WT) and mutant ROS1 kinase domains to explore the structural changes and interactions.

Results: The initial model of the human ROS1 crystal structure was constructed, incorporating missing loop residues and then utilized for the MD simulation studies. The examination of conformational changes in WT, G2032R, and D2033N mutant ROS1 proteins involved observing alterations in the C-alpha protein. We observed that the mutations resulted in deviations in the MD trajectory over the 500 ns period. Consequently, the MD simulations unveiled significant conformational changes induced by the G2032R and D2033N mutations, affecting protein stability and dynamics, particularly in regions such as the ATP binding and active sites.

Conclusion: Our study constructed an initial model of the human ROS1 and used it for MD simulation studies to examine the conformational changes in ROS1 mutants. Notably, our observations revealed that the mutations caused deviations in the MD trajectory. The G2032R and D2033N mutations significantly alter ROS1 structure, affecting its stability and dynamics, offering key insights into their role in cancer disease development.