News and Updates

Spectroscopy and computational modeling workshops announced

The Membrane Protein Structural Dynamics Consortium (MPSDC) is hosting two workshops on computational modeling and simulation, and spectroscopy methods. These will take place at the University of Chicago campus prior to the conference. Both of these workshops are designed for young investigators to learn some of the cutting edge tools and methodologies that are frequently used in contemporary membrane proteins research.

Computational Modeling Workshop and Mini-Symposium

May 6th – 7th 2014


Spectroscopy Workshop

May 7th 2014

Final program for Frontiers in Membrane Protein Dynamics 2014 released

The final program for Frontiers in Membrane Protein Structural Dynamics 2014 has been made available and posted to the website. To see the program, please click here.

Reminder: One more week to register early for Frontiers in Membrane Protein Structural Dynamics 2014

Frontiers in Membrane Protein Structural Dynamics

May 7th, 8th, and 9th, 2014*
Chicago Hilton Hotel, Chicago IL

This meeting is being hosted by the Membrane Protein Structural Dynamics Consortium (MPSDC), an NIH/NIGMS Glue Grant funded consortium which focuses on elucidating the relationship between structure, dynamics and function in a variety of membrane proteins.

The early registration deadline is on April 7th. After this date, registration is still possible but the fee schedule will increase significantly!

Register  Program

* The MPSDC will also host a NAMD mini-course on May 6th, plus satellite computational and spectroscopy workshops on May 7th. These will take place on the campus of the University of Chicago. More information will be released soon.

ABC Transporter paper by Tajkhorshid laboratory recommended on F1000Prime

One of our long-term projects onStructural Dynamics of ABC Transporters integrates computational, biochemical and spectroscopic approaches to understand the structural dynamics of the ATP binding cassette (ABC) transporters, which are associated with a number of human pathologies and play critical roles in the removal of cytotoxic agents.

Among the MPSDC participants in this project is Dr. Emad Tajkhorshid, whose contribution is applying molecular dynamics (MD) simulations integrating experimental constraints to develop structural models for key conformational states and characterize their inter-conversion during the transport cycle.

Tajkhorshid, together with postdoctoral researcher Mahmoud Moradi, recently published a paper on conformational transitions of ATP exporters which was recommended on the F1000Prime or “Faculty of 1000″ website. F1000 is a team of 5,000 Faculty Members – senior scientists and leading experts in all areas of biology and medicine — plus their associates who provide recommendations of important scientific articles, rating them and providing short explanations for their selections.

The publication by Moradi and Tajkhorshid, titled “Mechanistic picture for conformational transition of a membrane transporter at atomic resolution“, was published on November 19, 2013 in PNAS vol. 110, no. 47. The paper describes a nonequilibrium approach which they developed to characterize the conformational transition of MsbA, a member of the ATP-binding cassette exporter family, which is involved in transport of diverse substrates across the membrane. The F1000Prime recommendation, written by Qian Cui, tagged the publication as Good for Teaching, as having an Interesting Hypothesis, and for Technical Advance. Read the F1000 recommendation »

Dancing Proteins: Cell Membrane Transporter Motion May Revolutionize Drug Therapies (video)

The Beckman Institute at the University of Illinois at Urbana-Champaign produced the following video. In the video, Dr. Tajkhorshid desccribes how his laboratory has successfully simulated the molecular dance moves that a multidrug resistance membrane transporter undertakes as it pumps compounds out of a cell. This is the first time researchers have been able to simulate the motion of a complex membrane transporter in its native environment in full atomic detail and gives drug developers vital new targets to help combat drug-resistant cancers and other diseases.

Other plaudits

The popular NIH Biomedical Beat blog, which covers research news from NIGMS, featured the video on their website. As per the blog page, “In this video, Emad Tajkhorshid of the University of Illinois at Urbana-Champaign explains the molecular dance of ABC transporters, a family of molecular machines that utilize ATP to move substances across the cell membrane. Tajkhorshid and his team recently used computational methods to map the movements between two known structural models of MsbA, a bacterial version of a transporter in human cells that helps to export anti-cancer drugs. They then described the individual steps of the molecular motions during the transport cycle. Understanding the process at such a detailed level could suggest new targets for treating a range of diseases, including some drug-resistant cancers that often make more transporter proteins to kick out medications meant to kill them.”

Additionally, Tajkhorshid and Moradi were also featured in the University of Illinois News Bureau, in an article titled “Difficult dance steps: Team learns how membrane transporter moves.” The article helpfully describes the nature of the research and points to its innovation.

Photo taken from the University of Illinois News Bureau website. Photo by L. Brian Stauffer.

According to the article, “the new findings, reported in the Proceedings of the National Academy of Sciences, will help scientists figure out how other transporters work. The work also offers new insights into multi-drug-resistant (MDR) cancers, some of which use these transporters to export cancer-killing drugs.” Previously, it has been difficult to research large, membrane-bound proteins like MsbA because they are not easy to crystallize, and each crystal structure reflects only one of the many conformations of these shape-shifting proteins. This study marks “the first time that we are characterizing a very complex structural transition at atomic-level resolution for a large protein,” Dr. Tajkhorshid is quoted as saying.

Emad Tajkhorshid is Professor of Biochemistry, Biophysics, and Pharmacology and an affiliate of the Beckman Institute for Advanced Science and Technology at the University of Illinois at Urbana-Champaign.

CLC Channel/Transporter Family Project team combines computational and experimental methodologies in PNAS publication

The Conformational Dynamics in the CLC Channel/Transporter Family Project of the Membrane Protein Structural Dynamics Consortium (MPSDC) has published its first publication titled “Water access points and hydration pathways in CLC H+/Cl- transporters” in Proceedings of the National Academy of Sciences of the United States of America (PNAS). This Consortium Project is spearheaded by Principal Investigator Merritt Maduke. The laboratories of Marc Baldus, Emad Tajkhorshid, and Hassane Mchaourab are also collaborators in the Project’s ongoing research.

Water access points and hydration pathways in CLC H+/Cl- transporters

Figure 3. Entryways of water into the central hydrophobic region. (Han et al. 2013)

Abstract: CLC transporters catalyze transmembrane exchange of chloride for protons. Although a putative pathway for Cl has been established, the pathway of H+ translocation remains obscure. Through a highly concerted computational and experimental approach, we characterize microscopic details essential to understanding H+-translocation. An extended (0.4 µs) equilibrium molecular dynamics simulation of membrane-embedded, dimeric ClC-ec1, a CLC from Escherichia coli, reveals transient but frequent hydration of the central hydrophobic region by water molecules from the intracellular bulk phase via the interface between the two subunits. We characterize a portal region lined by E202, E203, and A404 as the main gateway for hydration. Supporting this mechanism, site-specific mutagenesis experiments show that ClC-ec1 ion transport rates decrease as the size of the portal residue at position 404 is increased. Beyond the portal, water wires form spontaneously and repeatedly to span the 15-Å hydrophobic region between the two known H+ transport sites [E148 (Gluex) and E203 (Gluin)]. Our finding that the formation of these water wires requires the presence of Cl explains the previously mystifying fact that Cl occupancy correlates with the ability to transport protons. To further validate the idea that these water wires are central to the H+ transport mechanism, we identified I109 as the residue that exhibits the greatest conformational coupling to water wire formation and experimentally tested the effects of mutating this residue. The results, by providing a detailed microscopic view of the dynamics of water wire formation and confirming the involvement of specific protein residues, offer a mechanism for the coupled transport of H+ and Cl ions in CLC transporters.

The results were published in Proceedings of the National Academy of Sciences of the United States of America, and are currently made available as an e-publication ahead of print. The citation is as follows:

Wei Han, Ricky C. Cheng, Merritt C. Maduke, and Emad Tajkhorshid.
Water access points and hydration pathways in CLC H+/Cl− transporters
PNAS 2013; published ahead of print December 30, 2013, doi:10.1073/pnas.1317890111

Learn more about this publication »


CLC transporters are biologically essential proteins that catalyze the transmembrane exchange of chloride for protons. The permeation pathway for chloride through the transporters has been well characterized. In this publication, Han et al. study the more elusive permeation pathway for protons. Through computational modeling, they show that water molecules can permeate deep inside the protein and form continuous wires. To test the hypothesis that these water wires mediate proton transport, they mutated residues predicted to impede water wire This research article reports results from the tightly coordinated efforts of a computational and an experimental lab brought together by the Consortium. The study addresses a critical question about the CLC transporter mechanism: how does H+ traverse the hydrophobic expanse of the CLC protein?formation and experimentally evaluated the effects of the mutations. The results from their concerted computational and experimental approach strongly support the role of water in proton transport by CLCs and provide a valuable framework for investigating their overall transport mechanism.

In a commentary piece published by PNAS this month, Mounir Tarek (National Center of Scientific Research at the University of Lorraine, France) describes the significance of this paper for future research of chloride channels, and highlights the fruitful combination of simulation and experimentation: “In PNAS, Han et al. used molecular dynamics (MD) simulations of the CLC-ecl, a CLC exchanger from Escherichia coli to specifically address this issue. The predictions of their calculations were tested by additional experiments, providing a robust description of the molecular prerequisites to proton transport in CLC-ecl and a framework for refining models of the Cl-/H+-coupled transport in CLCs.”

Indeed, this research article reports results from the tightly coordinated efforts of a computational and an experimental lab brought together by the Consortium. The study addresses a critical question about the CLC transporter mechanism: how does H+ traverse the hydrophobic expanse of the CLC protein? The MD simulations performed reveal water dynamics, water-wire formation, and side-chain conformational change not observed in any of the static crystal structures. The functional analyses validated predictions of the simulations and confirm the importance of water dynamics in the transport mechanism. The simulations further reveal that Cl- binding is critical for water-wire formation, thus providing a satisfying explanation for the puzzling experimental observation that Cl- occupancy correlates with the ability of CLCs to transport H+. These studies provide a crucial framework for understanding how H+ and Cl- binding and translocation steps are coordinated in the CLC transporters to control stoichiometric transport.

About the project

The CLC family of chloride channels and transporters is necessary for proper neuronal, cardiovascular, and epithelial function. One of the important aspects of this family of transport proteins is that minute changes in their amino acid sequence can result in a shift in their operation mode from a channel to a transporter. Studying the structural dynamics of CLCs can therefore provide fundamental information on the nature of structural and dynamical differences between passive channels and active transporters.

The Conformational Dynamics in the CLC Channel/Transporter Family project addresses the multiple structural conformations that underlie the dual function of ClC- proteins as both channels and coupled transporters. Using a combination of NMR (solution and solid-state) and molecular dynamics simulations, the multiple conformations that support closely-coupled, stoichiometric ion transport will be accessed by binding and unbinding its two ligands, (Cl- and H+). Additional efforts are made made to use conformation-specific ligands to “lock” CLC proteins in order to study these conformations by crystallography, EPR, and NMR.

Learn more about the project »

Publication by Schulten and Tajkhorshid featured as cover page for Journal of Computational Chemistry

Membrane Protein Structural Dynamics Consortium (MPSDC) team members Klaus Schulten and Emad Tajkhorshid from the Computational Modeling Core recently collaborated on an publication about a new Force Field Toolkit (ffTK), which minimizes common barriers to ligand parameterization through algorithm and method development, automation of tedious and error-prone tasks, and graphical user interface design. Distributed as a VMD plugin, ffTK facilitates the traversal of a clear and organized workflow resulting in a complete set of CHARMM-compatible parameters.

The article, titled Rapid parameterization of small molecules using the Force Field Toolkit was published in the Journal of Computational Chemistry and featured as a Cover Article for Volume 34, Issue 32. The journal provided the following caption along with the cover: “The Force Field Toolkit (ffTK), a new plugin for visual molecular dynamics by Christopher G. Mayne et al. on page 2757, aids users in the development of CHARMM/CGenFF-compatible force field parameters for small molecules. The primary function of ffTK is to generate quantum mechanical target data and optimize molecular mechanics force field parameters. The cover shows water interation profiles (center left), which are computed at each iteration of the partial atomic charge optimization, and torsion scans (left to right), which are used to compute potential energy surfaces during dihedral parameter optimization. ffTK also provides a suite of analytical tools to assess optimization metrics and parameter performance using embedded plotting utilities (background).”

Click the image to view the cover, and the inset text, in more detail:

First issue of MPSDC e-newsletter released

Fresh off the press: the first edition of the semi-annual Membrane Protein Structural Dynamics Consortium (MPSDC) e-newsletter!

The MPSDC e-newsletter brings together announcements, updates, features, new publications, and other MPSDC-relevant news blurbs in one email.

In the Winter 2013 newsletter, we announced the Frontiers in Membrane Protein Dynamics 2014 conference, and shared the exciting news of two scientists joining the Protein Expression / Purification core team. Additionally, we reviewed consortium progress and scientific advances discussed at 2013 Annual Meeting, and featured ongoing collaborative research in the laboratories of Hassane Mchaourab, Benoît Roux, and Emad Tajkhorshid.

View the Winter 2013 e-newsletter »

Do you want to receive the latest MPSDC updates via email? Sign up here!

Remember, you can also stay up the date with the MPSDC through our active Facebook page!

MPSDC to host Frontiers in Membrane Protein Dynamics 2014

Continuing with our successful annual meetings and workshops over the past three years, the Membrane Protein Structural Dynamics Consortium (MPSDC) announces the second Frontiers in Membrane Protein Dynamics meeting in 2014. The meeting, which will take place in the Chicago Hilton Hotel in the downtown Chicago loop area, is open to the public and will be our most extensive meeting to date.

Like our first Frontiers in Membrane Protein Dynamics meeting in 2012, the conference will consist of scientific sessions and poster presentations, and feature both Consortium members and external invitees. Unlike in previous years, however, Frontiers in Membrane Protein Dynamics 2014 will span three days of scientific discussion, organized into eight sessions covering topics at the edge of current developments in membrane protein structure, dynamics and function.

Additionally, we are thrilled to announce that Frontiers in Membrane Protein Dynamics 2014 will feature two keynote speakers. On May 7th, the meeting will be inaugurated by Dr. Robert Stroud, Professor of Biochemistry & Biophysics and Pharmaceutical Chemistry at the University of California at San Francisco. Then, on May 9th, Dr. Klaus Schulten, Swanlund Professor of Physics at the University of Illinois at Urbana Champaign and an active participant in the Consortium’s own Computational Modeling Core, will close the conference. Both Stroud and Schulten are renowned experts at the vanguard of membrane protein dynamics and their unique insights on the contemporary state of the scientific field will significantly enhance our discussions. Read more about Drs. Stroud and Schulten »

Last year’s annual meeting.
Click photo to enlarge.

Finally, we count a stellar roster of speakers covering a broad range of topics and techniques. A preliminary speaker list can be found here »

Up-to-date information about Frontiers in Membrane Protein Dynamics 2014, can be found at a stand-alone website portal dedicated exclusively to this meeting. In addition to hosting a registration form (mandatory for MPSDC members), we have included information about sponsorship opportunities, abstract submissions, a tentative program, Hilton Hotel room rates, and general information about the Chicago area to boot.

A registration fee schedule, based on Consortium affiliation, has been posted to the website. Upon registration, you will be redirected to an e-commerce gateway where payment for the meeting should be posted.

We invite you to visit the Frontiers in Membrane Protein Dynamics 2014 website, and let us know what you think! Please stay posted as we will be releasing more information to the website soon.

Visit the 2014 Frontiers in Membrane Protein Dynamics website »

MPSDC Protein Expression/Purification core adds two scientists to the team

We are pleased to announce that Drs. Francis Valiyaveetil and Andrzej Rajca and their research teams have officially joined the Consortium. Valiyaveetil and Rajca began their collaborations with the MPSDC as Associate Members, and are now participating as active members of the Membrane Protein Expression/Purification Core.

Dr. Francis Valiyaveetil is Assistant Professor of Physiology & Pharmacology at Oregon Health & Science University. The Valiyaveetil lab studies potassium channels, which are integral membrane proteins that catalyze the selective conduction of K+ ions across biological membranes. While a great deal of research has been focused on these channels, fundamental questions regarding the mechanism of ionic selectivity and gating remain. Valiyaveetil’s team has developed a unique combination of methods to address these questions. Their methods include the use of chemical synthesis to introduce precise chemical changes in the channels, x-ray crystallography to determine the structural effects and electrophysiology to determine the functional effects of these changes. Using this multidisciplinary approach they hope to explain the mechanism of ion selectivity and channel gating.

Dr. Andrzej Rajca is Charles Bessey Professor of Chemistry at University of Nebraska. The Rajca laboratory research interests lie in the area of organic and biomaterials chemistry. The underlying theme of the laboratory’s research is rational design and synthesis of new materials (molecules and polymers) with magnetic and optical properties. Rational design of new structures and materials (molecules and polymers) with targeted properties are implemented using the tools of organic synthesis, crystallography, magnetic resonance spectroscopy (NMR and EPR) and imaging (MRI), as well as magnetometry (SQUID), circular dichroism (CD) spectroscopy and multiangle light scattering (MALS).

According to Robert Nakamoto, PI of the Protein core, Rajca and Valiyaveetil will play a pivotal role in the core’s ongoing research activities: “Andrzej Rajca provides expertise in organic synthesis of nitroxide-containing compounds, and Frances Valiyaveetil is developing in vitro methods for synthesis and folding of membranous polypeptides. These investigators are collaborating with Protein Core members to develop methods for incorporation of spectroscopic labels directly into target proteins.”

Welcome, Andrzej and Francis!

2014 Meeting keynote lectures and tentative program announced

We are happy to present two keynote speakers for next year’s Frontiers in Membrane Protein Dynamics conference:

Our first speaker is Robert Stroud, Professor of Biochemistry & Biophysics and Pharmaceutical Chemistry at the University of California at San Francisco. At the Stroud lab, scientists seek to understand molecular mechanisms of certain key biological processes, as well as signal transduction between processes at the level of protein structure, dynamics, and mechanism. In addition to his posting at UCSF, Dr. Stroud is also the director of the Membrane Protein Expression Center, one of the centers funded by the NIH Common Fund Structural Biology Program. The MPEH develops and applies the latest innovative methods yielding structurally and functionally intact eukaryotic membrane proteins for drug development, and structural and functional characterization.

Our second keynote speaker is one of our very own Consortium members: Klaus Schulten, Swanlund Professor of Physics at the University of Illinois at Urbana Champaign. Professor Schulten is a full-time faculty member in the Beckman Institute and directs the Theoretical and Computational Biophysics Group. His professional interests are theoretical physics and theoretical biology. His current research focuses on the structure and function of supramolecular systems in the living cell, and on the development of non-equilibrium statistical mechanical descriptions and efficient computing tools for structural biology. Professor Schulten is a leader in the field of computational biophysics, having devoted over 40 years to establishing the physical mechanisms underlying processes and organization in living systems from the atomic to the organism scale. Schulten is a strong proponent of the use of simulations as a “computational microscope”, to augment experimental research, and to lead to discoveries that could not be made through experiments so far. The molecular dynamics and structure analysis programs NAMD and VMD, born and continuously developed in his group, are used today by many thousands of researchers across the world.

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