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Functional dependence of Lactose Permease on the Protonation State of Glu325 for Substrate Binding
Functional dependence of Lactose Permease on the Protonation State of Glu325 for Substrate Binding
Lactose Permease (LacY) is an integral membrane protein that belongs to the major facilitator super-family (MFS) and utilizes an existing proton gradient towards the cell to transport/shutle galactoside substrates in the same direction into the cell.
Abstract:
Membrane protein transporters govern important cellular processes and are therefore central to human health. To accomplish transport, these proteins rearrange their structures to alternatively expose an internal binding site to either side of the membrane. Recent advances in protein structural determination methods have resulted in a steadily increasing number of high-resolution structures of membrane transporters trapped in different intermediate states. However, to understand the underlying transport mechanism, the molecular details of the interactions between the protein and the transported compound need to be determined. We have used specialized simulation hardware and algorithms to simulate Lactose Permease (LacY) of Escherichia coli interactions to the natural galactoside substrate lactose in the context of the outward-open and occluded crystal structures.
Observations:
Observations:
We observed protonation-dependent differences in the structural dynamics of the protein-substrate interactions. Together, our simulations sought to answer the question why the galactoside sugar can bind only to a protonated state of the LacY transporter.
Molecular Dynamics | Steered Molecular Dynamics Algorithm
Membrane proteins in general are regarded as extremely potent drug targets covering approximately 60% of drugs currently on the market which justifies for a detailed understanding of their structure and mechanism of function. The Video of the left show the application of Steered Molecular dynamics to a group of atoms (Lactose Substrate) to explore the elastic properties and unfolding pathways.
The basic idea behind the applied SMD simulation is that we applied an external force to one or more atoms, which we refer to as SMD atoms. In addition, you can keep another group of atoms fixed and study the behavior of your protein under various conditions.
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