Poster #016, City of Hope
Allosteric Communication Networks Underlying Disease-Associated Mutations in DYRK1A
Mentors: Sneha Bheemireddy, PhD, PI: Nagarajan Vaidehi, MSc, PhD
Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) is a serine/threonine kinase in the DYRK family that is often involved in the regulation of brain development and cell proliferation. Mutations in DYRK1A are closely linked to increased risks of various cancers. The primary objective of this study is to elucidate the molecular mechanisms by which non-active-site disease-associated mutations (DAMs) disrupt the structure and function of DYRK1A. To achieve this, our methodology leverages molecular dynamics simulations to capture the conformational landscape of DYRK1A. We applied Bayesian Network Modeling of Molecular Dynamics Trajectories (BaNDyT) to the wild-type (WT), ATP-bound state to construct probabilistic graphical models that map the baseline, allosteric communication pathways coupling distal regulatory regions to the catalytic core. Finally, we analyzed the curated library of clinical DAMs distributed across DYRK1A to understand how genetic variants alter or collapse the established WT Bayesian network dependencies to decrypt pathways of long-range allosteric perturbation.