Coarse-Grained Modeling of the Dynamics and Allosteric Modulation of Hras Protein

HRAS acts as molecular switch by cycling between active (GTP-bound) and inactive (GDP-bound) state during signal transduction processes associated with cell growth and differentiation. The wealth of biochemical and structural data available for HRAS has identified critical regions in protein structure that plays crucial role in signalling. However, the mechanism by which active and inactive state transition occurs is not yet completely understood due to lack of experimentally determined intermediate structures. Also, the timescale at which these processes occur is currently beyond the reach of all-atom molecular dynamics simulations. In this talk, I will describe the dynamics of GDP and GTP bound form of HRAS with and without GEFs, using a transferable intermediate resolution model developed by us. In the model, the backbone is represented with atomic resolution but the sidechain with single bead and it has sufficient predictive power so that-- Starting from random initial configurations, the model properly folded 19 proteins (including a mutant sequence) in to native states containing β-sheet, α-helices and mixed α/β. The model is then used to predict the dynamics of HRAS. The predictions of the coarse-grained model are tested with different 100 ns simulations. We present intermediate states and demonstrate, among other results, that the opening of Switch I/β-2 region in HRAS-GTP is a thermally activated process and occurs in the absence of GEF.