Using large-scale molecular dynamics simulations and network analysis to illuminate the regulation mechanism of a disease-related protein kinase.
Eukaryotic protein kinases are highly dynamic enzymes with elaborate and specific interactions that control key processes in human cells. As they pass through their catalytic cycle, their regulation mechanism relies on their conformational plasticity and concerted motions that create a dynamic allosteric network of communication. Tyrosine Kinase 2 (TYK2) is a non-receptor tyrosine kinase that belongs to the Janus Kinase family (JAK) and is involved in various signaling pathways and plays a multifaceted role in the pathogenesis of several diseases, including autoimmune diseases and many types of cancer. To illuminate the atomic details of the TYK2 regulation mechanism it is vital to explore the dynamics and the structural changes throughout the different stages of its catalytic cycle which can be achieved with the application of Molecular dynamics (MD) simulations. We employed large-scale (μs), all-atom MD simulations and various analysis methods, including network analysis, to explore three different steps of the catalytic cycle of TYK2 (APO, ATP1Mg, ATP1Mgpeptide), compared to a polymorphism that is implicated in cancer.
Eukaryotic protein kinases are highly dynamic enzymes with elaborate and specific interactions that control key processes in human cells. As they pass through their catalytic cycle, their regulation mechanism relies on their conformational plasticity and concerted motions that create a dynamic allosteric network of communication. Tyrosine Kinase 2 (TYK2) is a non-receptor tyrosine kinase that belongs to the Janus Kinase family (JAK) and is involved in various signaling pathways and plays a multifaceted role in the pathogenesis of several diseases, including autoimmune diseases and many types of cancer. To illuminate the atomic details of the TYK2 regulation mechanism it is vital to explore the dynamics and the structural changes throughout the different stages of its catalytic cycle which can be achieved with the application of Molecular dynamics (MD) simulations. We employed large-scale (μs), all-atom MD simulations and various analysis methods, including network analysis, to explore three different steps of the catalytic cycle of TYK2 (APO, ATP1Mg, ATP1Mgpeptide), compared to a polymorphism that is implicated in cancer.
