[1P-68] Coarse-grained simulations of multiple intermediates along conformational transition pathways of multi-domain proteins
Molecular dynamics (MD) simulations are widely used to investigate structure-function relationship in biomolecules. Coarse-grained (CG) MD simulations is an inexpensive tool for studying large scale motions in proteins but they often require labour-intensive parametrization.We used the structure-based multi-basin Go-model for simulating conformational transitions between two structures of a protein. We defined intermediate structures by assuming that they have partial inter-domain native contacts. We developed an efficient scheme for parameter determination for the potential, combining short rounds of MD simulations with the Multistate Bennett Acceptance Ratio (MBAR) analysis, which allows to predict observables at unsimulated conditions. We applied the scheme to the enzyme Adenylate Kinase (AdK) and sampled multiple conformational transitions between its open and closed states. Moreover, by altering the model parameters we successfully sampled different transition pathways and characterized the structures of intermediate states along the path.