Structural dynamics of ABC transporters

The ATP-binding cassette transporters (ABC transporters) translocate substrates across membranes by ATP binding and hydrolysis. To understand the complex structural dynamics, transporters were investigated on three case studies: heterodimeric multidrug exporter TmrAB, cystic fibrosis transmembrane conductance regulator (CFTR), and manganese ion importer PsaBC. Anisotropic Network Model-Langevin Dynamics (ANM-LD) simulations were performed between four different conformations of TmrAB. The analysis for each transition revealed the allosteric couplings between the ATP binding in nucleotide binding domains (NBD) and extracellular gates on transmembrane domains (TMD). Transfer Entropy (TE) calculations showed that TMDs and NDBs of TmrAB become drivers at different stages during the translocation cycle. The ANM-LD simulations of dephosphorylated to phosphorylated CFTR transition revealed that the initial movements in the NBDs are followed by the movement of the gating areas in TM. The causal relationships between these movements were supported by TE calculations. CFTR potentiator drug Ivacaftor has been shown to have a global effect, mimicking the effects of ATP binding and gating residues. Corrector drug Lumacaftor has a local effect on TM1, 2, 3, and 6. The dynamics of PsaBC was characterized using TE calculations, and testable predictions were made. Four possible gating residues were identified along with an allosteric pocket on TM8. Finally, TE calculations of many ABC transporters showed the differences and similarities between different types. Type I transporters were shown to be controlled by TMDs in the inward facing (IF) conformation, and NBDs and substrate binding protein (SBP) in the outward facing (OF) conformation. Type II transporters were always driven by NBDs, regardless of conformation. Type IV transporters showed more variability, but for most, TMDs are driving for IF and NBDs are driving for OF conformations. Dynamic characterization methods show potential in classifying ABC transporters.