Tag | Beckstein Lab

. . . . .
Tag Archives: transporter
Tsong Prize awarded to Taylor Colburn

Tsong Prize awarded to Taylor Colburn

Undergraduate student Taylor Colburn was awarded the 2017 Tsong Prize for Undergraduate Research in the Department of Physics at Arizona State University for his work on Simulating the conformational transitions of the transmembrane symporter Mhp1.

Comment Continue Reading →
Molecular basis of ion translocation in sodium/proton antiporters

Molecular basis of ion translocation in sodium/proton antiporters

We studied the process of sodium/proton antiport in the NapA transporter. Through a combination of X-ray crystallography, biochemistry and computer simulations we could show that the antiporter undergoes a large conformational transition that resembles a *elevator*-like movement whereby a single domain moves up- and down through the membrane and carries a sodium ion with it.

Comment Continue Reading →
Project: Simulation of transmembrane transport

Project: Simulation of transmembrane transport

A central process in maintaining life is the transport of ions or small molecules such as nutrients across the cell membrane by secondary active transporter proteins. In this project you will use molecular dynamics (MD) computer simulations to study some of the fundamental principles by which transporters act as molecular machines that transduce energy through macromolecular conformational changes. In particular, you will attempt to solve a molecular puzzle : how can a large transported molecule fit through a transporter protein that according to experimental structural data appears too narrow?

Comment [2] Continue Reading →
Project: Transport of divalent cations

Project: Transport of divalent cations

Divalent cations such as zinc or magnesium are essential for living organisms but the mechanisms by which they are transported into and out of the cell are not well understood at the molecular level. Classical molecular dynamics simulations of divalent ions are challenging because the high electric field strength near the ion leads to polarization effects that are not accurately accounted for in standard MD force fields. In this project you will explore alternative models for simulating divalent ions in order to find models that combine computational speed with sufficient accuracy to study transport of divalent ions with transporter proteins.

Comment Continue Reading →
Biophysical Society Travel Award for David Dotson

Biophysical Society Travel Award for David Dotson

David Dotson was awarded a 2015 Education Committee Travel Award to present his research on Recent Structures and molecular dynamics simulations offer new perspective on Na+/H+ antiporters at the 59th Annual Meeting of the Biophysical Society in Baltimore, MD.

Comment Continue Reading →
Crystal structure of the sodium-proton antiporter NhaA dimer and new mechanistic insights

Crystal structure of the sodium-proton antiporter NhaA dimer and new mechanistic insights

A new crystal structure of the Escherichia coli NhaA dimer reveals a previously unidentified salt bridge between two highly conserved residues at the putative binding site. The combination of structural data with molecular dynamics simulations yields new insights into the transport mechanism.

Comment Continue Reading →
Molecular mechanism of ligand recognition by the Mhp1 transporter

Molecular mechanism of ligand recognition by the Mhp1 transporter

The hydantoin transporter Mhp1 is a sodium?coupled secondary active transport protein of the nucleobase?cation?symport family and shares the widespread 5?helix inverted repeat transporter architecture. Our previous work showed Mhp1 functions according to the alternating access mechanism. In our new paper in EMBO J , we elucidate detailed events of substrate binding, through a combination of crystallography, molecular dynamics, site?directed mutagenesis, biochemical/biophysical assays, and the design and synthesis of novel ligands.

Comment Continue Reading →
Bedabrata Choudhury

Bedabrata Choudhury

In Fall 2014, Bedabrata started a rotation project on the molecular mechanism of temperature sensing. The goal of this project is to study the heat-sensitive TRPV1 ion channel with molecular dynamics (MD) simulations and identify regions or conformations of the protein that are sensitive to temperature changes. The work will be carried out in collaboration with the experimental lab of Dr van Horn in the Department of Chemistry and Biochemistry.

Comment Continue Reading →
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.

Comment Continue Reading →
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.

Comment Continue Reading →
A two-domain elevator mechanism for sodium/proton antiport

A two-domain elevator mechanism for sodium/proton antiport

In a combined X-ray crystallography/biochemistry/molecular simulation study published in Nature we present the structure of the sodium/proton antiporter NapA in its outward facing conformation. Together with the inward facing conformation of the related transporter NhaA we can now understand the conformational changes required for the sodium/proton antiport mechanism.

Comment Continue Reading →
X-ray crystallography and Simulations

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.

Continue Reading →
Long Liang

Long Liang

Long Liang majored in Biology in his undergraduate study, and shifted to Physics for his PhD study. He hopes to combine his background in Biology and Physics to understand life in terms of the more fundamental Physical laws. In his rotation project he worked on constructing a validated model of a human neurotransmitter transporter. Long is now part of the Complex Materials Group and works on his PhD under Professor Yang Jiao.

Comment Continue Reading →
David Dotson

David Dotson

David worked as a research software engineer in the lab. He left in June 2017 for industry.

Comment Continue Reading →
Atomically detailed molecular dynamics simulations

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.

Continue Reading →
The alternating access mechanism in Mhp1

The alternating access mechanism in Mhp1

Secondary transporters couple the free energy stored in an ionic gradient to the movement of solutes across the cell membrane. The coupling enables these transmembrane proteins to transport small molecules against their own concentration gradients. The transporters function by cycling between different conformational states in which access to the central binding site is switched from the extracellular solution to the intracellular compartment. Using experimental and computational approaches we could visualize for the first time how this process occurs for a secondary transporter.

Continue Reading →
Transporters

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.

Continue Reading →
Simulations of membrane proteins

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.