Protein kinases, enzymes which modify proteins through phosphorylation, are important for the regulation of cell growth, proliferation, and immune response. One such kinase is Abl1, which is often involved in the spread of certain cancers when it is present in a hyperactive state. It has previously been discovered that Abl1 inhibitors are an effective treatment for cancers like myeloid leukemia. Thus, understanding Abl1 conformations can lead to the design of more effective inhibitors. Abl1 transitions between active and inactive states through conformational changes (Figure 1). Previous experiments have used NMR spectroscopy to show that Abl1 can interconvert between a first and second inactive state, in addition to its active state. Molecular dynamics simulations have been useful for analyzing these changes on the nanosecond time scale, allowing for a more detailed understanding of conformational transitions. However, there has yet to be work done modeling the change from the first active state to the first inactive state, which could reveal more “hidden” conformations. These hidden conformations could expose new ways in which an inhibitor can bind to the protein, allowing for the development of more effective drugging. In this project, we have elucidated the mechanism by which the first active state and the first inactive state of the Abl1 kinase interconvert through molecular dynamics and metadynamics. After analyzing longer-time Abl1 conformational changes, we were able to reveal the dynamics into the first inactive state and out of the first active state for the first time. These findings will hopefully serve as a catalyst for future work on more effective kinase-inhibiting drugs.
Anjali R Srinivasan, Alberto Lopez Resendiz,
"Analyzing the Dynamics of the ABL1 Protein Kinase"
(2022).
Summer Research Symposium.
Brown Digital Repository. Brown University Library.
https://doi.org/10.26300/87zv-p252
Each year, Brown University showcases the research of its undergraduates at the Summer Research Symposium. More than half of the student-researchers are UTRA recipients, while others receive funding from a variety of Brown-administered and national programs and fellowships and go …
