Beckstein Lab

. . . . .

Transporters

Transporter proteins are used by cells to “pump” molecules or ions into or out of the cell. They are present in all cells (digestive system, nervous system, blood, …) with important roles in metabolism. Secondary active transporters move their substrates against a electrochemical potential gradient and therefore couple uptake/excretion to an energetically favourable flow of sodium ions or protons into the cell.

Transporters

Ion channels

Ion channels are membrane proteins that play major roles in fast signal conduction in nerve cells and the brain. They consist of a water filled pore through which ions can flow. An external signal, such as a change in membrane potential or the binding of a neurotransmitter, can switch the pore from “open” to “closed”, a process termed gating.

Ion channels

Atomically detailed molecular dynamics simulations

Using molecular dynamics (MD) computer simulations we can study membrane proteins in atomic detail, down to the movements of individual water molecules. For example, the Mhp1 transporter protein shown here switches between three different functional states: A: outward facing; B: occluded; C: inward facing — as predicted byt the alternating access model.

Atomically detailed molecular dynamics simulations

Protein hydration

Proteins interact with the surrounding water, and water molecules influence the binding of ligands and drugs to proteins profoundly. Coarse-grained analysis of water dynamics can be facilitated with a network model of hydration as shown here for the retinol binding protein CRBPII.

Protein hydration

X-ray crystallography and Simulations

Structures of membrane proteins can be obtained by the experimental technique of X-ray crystallography. However, proteins are typically not crystallized in their native environment, the lipid membrane. Molecular dynamics simulations of the protein in the membrane provide a realistic model of the interactions between transporter and lipid bilayer.

X-ray crystallography and Simulations

Simulations of membrane proteins

Many proteins in the living cell can be understood as molecular machines that use a source of energy to produce mechanical or chemical work. My lab’s primary interest is in those proteins located in the cell membrane that move nutrients, signalling molecules, or waste products into and out of the cell. We study their molecular mechanisms of action by detailed molecular dynamics simulations, which provide a “movie” of full atomic detail of a working protein.

Current areas of interest focus on the mechanisms of secondary active transport; methods to accurately simulate macromolecular transitions that are crucial in understanding ligand binding, gating in ion channels, or the translocation of substrates through the cell membrane; and the role of water in confined geometries, for instance in ion channel gating mechanisms, ligand discrimination, or drug binding.