Cell membrane creates a barrier that separates the inside of the cell
from the outside, thereby preventing the passage of most hydrophilic
molecules. Membrane transporters are designed to transfer materials
across this barrier. They perform a wide range of biological functions,
from the uptake of nutrients in bacteria to the generation of membrane
potential in human cells. By coupling to energy sources such as ATP
hydrolysis, some transporters can actively pump the substrates across
the membrane against the concentration gradient. Conformational change
is the key step in the functioning of membrane transporters. According
to the “alternating access model”, membrane transporters adopt an
outward- or an inward-facing conformation, and the alternating
transitions between these two conformations drive the translocation of
the substrate. Although in recent years a growing number of transporter
structures have become available, the key question – how the proteins
change their shape from one state to the other – remains largely
elusive. Through computational modeling and simulations, the proposed
study aims to quantitatively characterize the transition between the
two conformations. We will apply advanced sampling techniques to
identify the transition pathway at atomic resolution, and to reveal the
thermodynamics and kinetics of the transition, making it possible to
predict experimental observables such as the net substrate transport
rate. The outcome of this project will thus provide important insight
into the mechanism of these molecular machines.
