Abstract
Lactose permease (LacY) has become a model system for monitoring substrate transport across the lipid bilayer. As a result of considerable experimental and structural data, the underlying molecular determinants for substrate specificity and affinity, as well as a mechanism for symport have been postulated. We have now monitored LacY structural dynamics in a lipid environment for 10 microseconds by using molecular dynamics simulations of a recent mutant LacY crystal structure trapped in a novel occluded state with bound high-affinity substrate. On this timescale, the sugar molecule exits the protein and re-enters. Therefore, the accompanying dynamics provide important clues regarding substrate specificity. In particular, Phe27 and neighboring lipid molecules assist in directing the sugar molecule to its binding position. In addition, simulations of substrates with different binding affinities enabled characterization of the structural framework governing substrate affinity in LacY.
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