Professor Peter Tieleman from Dept. Biological Sciences, University of Calgary, AB, Canada will give a talk Jeudi 25 avril 2013, 10h00 in the INTS conference room.
The subject is : Computational studies of ABC transporters
ABC transporters are ATP-driven machineries that translocate a wide variety of substrates across
membranes. Prokaryotic and eukaryotic ABC transporters, despite their different functional roles, share a
common structural core that consists of two transmembrane domains (TMDs) coupled to two highly
conserved nucleotide-binding domains (NBDs). For these transporters an alternating access mechanism
has been proposed in which the transmembrane cavity is exposed to one side of the membrane for
substrate binding first, and then to the other side for substrate release. This TMD motion is tightly coupled
with the dimerization and the dissociation of the NBDs, controlled by ATP-binding and -hydrolysis.
In this talk, I will discuss how models of eukaryotic ABC transporters for which no structures are available
give insight into aspects of their function and mechanism. I will also present results on molecular
dynamics simulations of the bacterial transporter TM287/288, with a focus on the role of ATP binding at
the degenerate site. Our aim is to characterize the structural differences at the NBD interface induced by
the presence of the nucleotide and to study how the dynamics of the transporter changes as a function
of the nucleotide-bound state. We have performed molecular dynamics (MD) simulations, for a total
simulation time of ca. 10 microseconds on the structure of TM287/288 in different nucleotide-bound
states. Our results show that when ATP is not present at the consensus site, the simulation systems with
and without ATP at the degenerate site do not dissociate at the NBD level, but reach an intermediate
state in which contacts between the two NBDs are observed. However, the pattern of interactions at the
NBD interface in the two systems is different and can be ascribed to either the presence or the absence
of the nucleotide at the degenerate site.