a detailed modular analysis of heat-shock protein dynamics under acute and chronic stress and its implication in anxiety disorders热休克蛋白的详细的模块化分析动力学在急性和慢性压力和焦虑障碍的含义.pdfVIP

A Detailed Modular Analysis of Heat-Shock Protein Dynamics under Acute and Chronic Stress and Its Implication in Anxiety Disorders K. Sriram1,2,3, Maria Rodriguez-Fernandez1,2, Francis J. Doyle, III1,2* 1 Institute of Collaborative Biotechnologies, University of California Santa Barbara, Santa Barbara, California, United States of America, 2 Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, California, United States of America, 3 Indraprastha Institute of Information Technology (IIIT), Delhi, India Abstract Physiological and psychological stresses cause anxiety disorders such as depression and post-traumatic stress disorder (PTSD) and induce drastic changes at a molecular level in the brain. To counteract this stress, the heat-shock protein (HSP) network plays a vital role in restoring the homeostasis of the system. To study the stress-induced dynamics of heat-shock network, we analyzed three modules of the HSP90 network—namely trimerization reactions, phosphorylation– dephosphorylation reactions, and the conversion of HSP90 from an open to a closed conformation—and constructed a corresponding nonlinear differential equation model based on mass action kinetics laws. The kinetic parameters of the model were obtained through global optimization, and sensitivity analyses revealed that the most sensitive parameters are the kinase and phosphatase that drive the phosphorylation–dephosphorylation reactions. Bifurcation analysis carried out with the estimated kinetic parameters of the model with stress as bifurcation parameter revealed the occurrence of ‘‘mushroom’’, a type of complex dynamics in which S-shaped and Z-shaped hysteretic bistable forms are present together. We mapped the molecular events responsible for generating the mush