Molecular simulations of conformational transitions in biomolecules using a novel computational tool

The function of biological macromolecules is inherently linked to their complex conformational behaviour. As a consequence, the corresponding potential energy landscape encompasses multiple minima. Some of the intermediate structures between the initial and final states can be characterized by experimental techniques. Computer simulations can explore the dynamics of individual states and bring these together to rationalize the overall process. A novel method based on atomistic structure-based potentials in combination with the empirical valence bond theory (EVB-SBP) has been developed and implemented in the Amber package. The method has been successfully applied to explore various biological processes. The first application of the EVB-SBP approach involves the study of base flipping in B-DNA. The use of simple structurebased potentials are shown to reproduce structural ensembles of stable states obtained by using more accurate force field simulations. Umbrella sampling in conjunction with the energy gap reaction coordinate enables the study of alternative molecular pathways efficiently. The main application of the method is the study of the switching mechanism in a short bistable RNA. Molecular pathways, which connect the two stable states, have been elucidated, with particular interest to the characterisation of the transition state ensemble. In addition, NMR experiments have been performed to support the theoretical findings. Finally, a recent study of large-scale conformational transitions in protein kinases shows the general applicability of the method to different biomolecules.