| ATP Binding Cassette proteins constitute one of the largest families of proteins and are involved in facilitating the transport of various compounds across cellular membranes. These transporters typically consist of two transmembrane domains (TMD) that form the pathway for transport, and two cytoplasmic nucleotide-binding domains (NBD) that power transport by binding and hydrolyzing ATP. In spite of remarkable recent progress in the structural and biochemical characterization of ABC proteins, details of the mechanism by which they function remain unclear. In this work, structural changes that may occur during the catalytic cycle of ABC transporters were investigated using computational approaches, primarily molecular dynamics (MD) simulations. Two key aspects were probed, namely: the effect of MgATP and MgADP on the conformational state of the NBD, and the general mechanism of conformational coupling between the NBD and the TMD. The results indicate that MD simulation can be a viable tool for modelling alternative states of a protein, based on the availability of the crystal structure of a single state. For instance, by introducing MgATP into the active sites, a transition from a semi-open state to a closed state was observed in dimeric forms of two ABC transporters - MalK and BtuCD. Furthermore, the atomistic MD simulations revealed local structural changes that may play important roles in conformational coupling during three key steps of the catalytic mechanism: the binding of ATP, the hydrolysis of ATP, and the release of ADP. |
