Molecular simulation of conformational transitions in biomolecules using a combination of structure-based potential and empirical valence bond theory.

The functions of biological macromolecules are inherently linked to their complex conformational behaviour. As a consequence of this complexity, the corresponding potential energy landscapes encompass multiple minima. Some of the intermediate structures between 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. Here, we show that the experimental structures can be exploited to define simple yet accurate atomistic structure-based potentials (SBP) that describe individual conformational states. These individual states can then be coupled by using the empirical valence bond (EVB) model. The overall energy landscape can easily be parameterised to reproduce available kinetic and thermodynamic data. We illustrate the procedure by applying the EVB-SBP method to study base flipping in B-DNA. Simple SBP is shown to reproduce structural ensembles obtained by using more refined force field simulations. Umbrella sampling in conjunction with the general energy gap reaction coordinate enables us to study alternative molecular pathways efficiently. We find that base rotation takes place via both grooves of the B-DNA with a marked preference for the major groove pathway. We also identify an unusual high-energy off-pathway intermediate that may appear if the base closing process is initiated from a syn base.