Giray Enkavi, Jing Li, Paween Mahinthichaichan, Po-Chao Wen, Zhijian Huang,
Saher A. Shaikh, and Emad Tajkhorshid.
Simulation studies of the mechanism of membrane transporters.
In Luca Monticelli and Emppu Salonen, editors, Biomolecular
Simulations, volume 924 of Methods in Molecular Biology, pp. 361-405.
Humana Press, 2013.
ENKA2013-ET
Membrane transporters facilitate active transport of their specific substrates, often against
their electrochemical gradients across the membrane, through coupling the process to
various sources of cellular energy, for example, ATP binding and hydrolysis in primary
transporters, and pre-established electrochemical gradient of molecular species other than
the substrate in the case of secondary transporters. In order to provide efficient energy-
coupling mechanisms, membrane transporters have evolved into molecular machines in
which stepwise binding, translocation, and transformation of various molecular species are
closely coupled to protein conformational changes that take the transporter from one
functional state to another during the transport cycle. Furthermore, in order to prevent the
formation of leaky states and to be able to pump the substrate against its electrochemical
gradient, all membrane transporters use the widely-accepted ``alternating access
mechanism", which ensures that the substrate is only accessible from one side of the
membrane at a given time, but relies on complex and usually global protein conformational
changes that differ for each family of membrane transporters. Describing the protein
conformational changes of different natures and magnitudes is therefore at the heart of
mechanistic studies of membrane transporters. Here, using a number of membrane
transporters from diverse families, we present common protocols used in setting up and
performing molecular dynamics simulations of membrane transporters and in analyzing
the results, in order to characterize relevant motions of the system. The emphasis will be
on highlighting how optimal design of molecular dynamics simulations combined with
mechanistically oriented analysis can shed light onto key functionally relevant protein
conformational changes in this family of membrane proteins.
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