NPP Seminars 2012-13
15 August 2011
next NPP seminar Wed 8th May 4pm
Wednesday 8th May 4pm H.O.Schild Lecture Theatre, Medical Sciences Bldg
Professor Peter Tieleman
Dept. Biological Sciences, University of Calgary, Alberta, Canada
Title: Computational studies of ABC transporters
Host: Paola Vergani email@example.com
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.