Session: Undergraduate Research Posters: Biochemistry:

Our research focuses on studying communication pathways in ERK2 to provide an insight into dynamics within the protein and its interactions with other complexes. Extracellular signal-regulated kinase 2 (ERK2) was chosen to validate our new method derived from molecular dynamics simulations. ERK2 is a major regulator in cell proliferation and is an important drug target. The goal of our research is to gain better understanding of mutations and their effect on allosteric relationships in the protein and their connection with disease states. We present a new method for calculation of transfer entropy from the variance-covariance matrix of protein fluctuations that provides rapid and efficient results compared with current methods that require very long simulations and approximate methods are not applicable in mutation studies. We validate our method on a series of molecular dynamics simulations of ERK2 in its active and inactive states and four auto-activating mutants. We find that the inactive state shows information flow among the important structural regions that undergo rearrangement upon kinase activation. The active state shows that the ATP binding site drives the substrate binding sites, providing insights into the mechanism for binding and reaction of the kinase. Mutant L73P shows greater driving behavior of the activation lip than the other states and the pathways provide evidence that the L73P mutant may operate by a different mechanism than the other mutants. Findings from our computational data match existing literature on ERK2, confirming that our new method can be used for rapid and reliable calculation of transfer entropy and successfully applied to mutation studies. We also present a new understanding of the role of the N-terminal region, and especially the P-loop, in the allosteric communication pathways of ERK2 which we expect to be of interest in ongoing drug design efforts.

Dr. Daniel Barr

Application Scientist, Optibrium

Appearances