Mahmoud Moradi and Emad Tajkhorshid.
Mechanistic picture for conformational transition of a membrane
transporter at atomic resolution.
Proceedings of the National Academy of Sciences, USA,
110:18916-18921, 2013.
(PMC: PMC3839739)
MORA2013A-ET
During their transport cycle, ATP-binding cassette (ABC) transporters undergo large-scale
conformational changes between inward- and outward-facing states. Using an approach
based on designing system-specific reaction coordinates and using non-equilibrium work
relations, we have performed extensive all-atom molecular dynamics simulations in the
presence of explicit membrane/solvent to sample a large number of mechanistically
distinct pathways for the conformational transition of MsbA, a bacterial ABC exporter
whose structure has been solved in multiple functional states. The computational approach
developed here is based on (i) extensive exploration of system-specific biasing protocols
(e.g., using collective variables designed based on available low-resolution crystal
structures) and (ii) using nonequilibrium work relations for comparing the relevance of the
transition pathways. The most relevant transition pathway identified using this approach
involves several distinct stages reflecting the complex nature of the structural changes
associated with the function of the protein. The opening of the cytoplasmic gate during the
outward- to inward-facing transition of apo MsbA is found to be disfavored when the
periplasmic gate is open and facilitated by a twisting motion of the nucleotide-binding
domains that involves a dramatic change in their relative orientation. These results
highlight the cooperativity between the transmembrane and the nucleotide-binding
domains in the conformational transition of ABC exporters. The approach introduced here
provides a framework to study large-scale conformational changes of other membrane
transporters whose computational investigation at an atomic resolution may not be
currently feasible using conventional methods.
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