Research 3 | Beckstein Lab

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Sampling macromolecular transitions

Sampling macromolecular transitions

While equilibrium MD is considered the most robust approach to simulating macromolecular conformational changes, conformational transitions are rare events that take place on much faster timescales than the waiting times spent in metastable equilibrium states. Equilibrium simulations thus spend relatively little time sampling actual transition events. Fast transition path sampling methods seek to mitigate the rare event sampling problem, though the full extent to which biased or coarse-grained approaches can replicate physical ensembles of transitions is unknown.

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Flexible Gates Generate Occluded Intermediates in the Transport Cycle of LacY

Flexible Gates Generate Occluded Intermediates in the Transport Cycle of LacY

We show that one of the best-studied secondary active transporters, the lactose permease LacY, goes through an occluded conformation during its transport cycle. We propose an atomically detailed model of the apo-occluded state. The simulations predict the formation of a transient salt bridge that has been hypothesized in the canonical model for transport of LacY. The simulations are validated by comparison to experimental EPR DEER data, using a new approach to simulate spin-label distance distributions through post-processing of molecular dynamics trajectories. We also define a set of order parameters that consistently classify all known MFS transporter structures as outward-open, occluded, or inward-open conformations.

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Influence of lipids on transmembrane transport proteins

Influence of lipids on transmembrane transport proteins

We are reviewing the evidence for direct effects of lipids on the transport properties of ion channels and active transporters. For ion channels it has been convincingly shown that specific lipid-protein interactions can directly affect their function. For transporters, the evidence is more ambiguous. In all areas, however, the use of computer simulations extends the way in which we understand protein-membrane interactions.

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