title: Transition path theory analysis of c-Src kinase activation.
abstract: Nonreceptor tyrosine kinases of the Src family are large multidomain allosteric proteins that are crucial to cellular signaling pathways. In a previous study, we generated a Markov state model (MSM) to simulate the activation of c-Src catalytic domain, used as a prototypical tyrosine kinase. The long-time kinetics of transition predicted by the MSM was in agreement with experimental observations. In the present study, we apply the framework of transition path theory (TPT) to the previously constructed MSM to characterize the main features of the activation pathway. The analysis indicates that the activating transition, in which the activation loop first opens up followed by an inward rotation of the αC-helix, takes place via a dense set of intermediate microstates distributed within a fairly broad "transition tube" in a multidimensional conformational subspace connecting the two end-point conformations. Multiple microstates with negligible equilibrium probabilities carry a large transition flux associated with the activating transition, which explains why extensive conformational sampling is necessary to accurately determine the kinetics of activation. Our results suggest that the combination of MSM with TPT provides an effective framework to represent conformational transitions in complex biomolecular systems.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637;
authors.forename: Yilin
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA 94305; Simulation of Biological Structures NIH Center for Biomedical Computation, Stanford University, Stanford, CA 94305.
authors.forename: Diwakar
authors.initials: D
authors.lastname: Shukla
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA 94305; Simulation of Biological Structures NIH Center for Biomedical Computation, Stanford University, Stanford, CA 94305.
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Pande
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637; roux@uchicago.edu.
authors.forename: Benoît
authors.initials: B
authors.lastname: Roux
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D020134:Catalytic Domain; D004789:Enzyme Activation; D008390:Markov Chains; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D013816:Thermodynamics; D019061:src-Family Kinases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases
keywords: Markov state models; conformational transition; transition path theory