University of Illinois professor and MPSDC team member Emad Tajkhorshid, along with co-PIs Chad Rienstra (Chemistry) and James Morrissey (Biochemistry) have been awarded a Director’s Transformative Research Award from the National Institutes of Health for their highly creative approach to the study of cell membrane lipids.
Membrane proteins are abundant in eukaryotic cells and play important roles in a great many biological processes ranging from cell adhesion and recognition to energy production to signaling cascades.
Membrane proteins make up more than half of the targets for currently approved drugs, which underscores their relevance to human disease but less is known about the membrane lipids that interact with proteins and ligands.
It is becoming increasingly clear that lipids are effector molecules that modulate and/or directly carry out essential biological functions at very different rates depending on what types of lipids are present. Some examples include blood clotting, cell recognition (in immunological response especially), ion conduction (important for neuronal function and viral infection), transport of drugs across the membrane, and pain response.
A potential long-term application is the development of more effective drugs that target biological membranes. Since about 60% of the drugs on the market target membrane-bound proteins, a better understanding of lipid structure and dynamics could greatly improve the efficacy of drug design efforts by modeling the interactions that take place. This would have broader impacts on understanding all the biological functions above and potentially to address the resulting pathologies or diseases. Better blood thinners would help to ameliorate deep vein thrombosis, heart attacks and strokes. Improved modeling of immunological cell recognition and viral life cycles would help to address infectious diseases ranging from influenza to HIV/AIDS. Understanding how drugs are transported would aid in the development of better antibiotics. The project aims to develop a toolkit of methods that would be available to researchers addressing this range of problems and many others.
The High-Risk, High-Reward Research (HRHR) program, supported by the National Institutes of Health (NIH’s Common Fund) awarded twelve transformative research awards funded by the Director’s office. The awards span the broad mission of the NIH and include groundbreaking research.
Read more about the project here: link
Model of LeuT alternating access inferred from the crystal structures.
This week, the Transport Cycle in Neurotransmitter Uptake Systems bridging project of the Membrane Protein Structural Dynamics Consortium (MPSDC) published an important article in Nature Structural & Molecular Biology on the bacterial leucine transporter (LeuT), a transporter which is structurally and functionally similar to neurotransmitter transporter proteins that direct neurotransmitters from synapse and terminal nerve signaling. The publication, titled “Conformational dynamics of ligand-dependent alternating access in LeuT,” was spearheaded by Vanderbilt graduate student Kelli Kazmier and Professor of Molecular Physiciology & Biophysics Hassane Mchaourab, and also featured collaboration by Consortium colleagues Jonathan Javitch, Harel Weinstein, and Benoît Roux.
The Transport Cycle in Neurotransmitter Uptake Systems project explores the conformational changes and dynamic properties relevant to function in Neurotransmitter transporters translocation cycle using a combination of computational, functional, and spectroscopic approaches. Using the recently determined crystal structure of a prokaryotic leucine transporter (LeuT), the scientists collaborating in this project are modeling the transport mechanisms of these proteins.
In this study, Mchaourab and colleagues used spectroscopic tools to make dynamic measurements in LeuT, in order to elucidate sodium- and leucine-dependent conformational This work highlights the importance of assessing the mechanistic identity of crystal structures, demonstrates the importance of dynamics in understanding function and realizes the vision of the consortium in integrating teams of scientists towards defining mechanistic principles of membrane proteins.changes in the transporter. The results identify the structural motifs that underlie the shift of LeuT between its various states – outward-facing, inward-facing and occluded. The conformational changes reported present a dynamic picture of the alternating-access mechanism of LeuT and NSSs that is different from the inferences reached from currently available structural models.
The publication marks a significant advance for the project’s research objectives, and is demonstrative of the cutting-edge collaborations between experimentalists and computationalists within the Consortium. According to Mchaourab, this work “highlights the importance of assessing the mechanistic identity of crystal structures, demonstrates the importance of dynamics in understanding function and realizes the vision of the consortium in integrating teams of scientists towards defining mechanistic principles of membrane proteins.”
The publication was also featured in Research News @ Vanderbilt. Click to read »
MPSDC Team Member Robert Nakamoto, who leads the Consortium’s Protein Production/Expression Core, is this year’s Chair of the 2014 Biophysical Society Program Committee. Nakamoto was interviewed several times by Biophysical Society TV for the occasion of the 2014 Biophysical Society meetings. You can check out the interviews below:
Biophysical Society president and MPSDC Team Member Francisco Bezanilla was interviewed today by Biophysical Society TV. You can check out the interview below:
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:
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 »
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The 2014 International Biophysics Congress, which is taking place in Brisbane, Australia this year, will have the pleasure of hosting none other than MPSDC Director Dr. Eduardo Perozo.
Along with three other scientists, Perozo has been nominated as a plenary speaker for this conference hosted by the Australian Society for Biophysics (ASB) and the International Union of Pure and Applied Biophysics (IUPAB).
“IUPAB 2014″ will feature an outstanding scientific program and a stimulating social program. Attending this Congress will be highly scientifically rewarding, as well as a terrific opportunity to visit Australia. The meeting will be held from August 3 – 7, 2014 at the Brisbane Convention & Exhibition Centre.
Visit the IUPAB 2014 Conference website »
Membrane Protein Structural Dynamics Consortium (MPSDC) team member Hassane Mchaourab was recently featured in the Vanderbilt University Medical Center Reporter, along with a team of scientists who have linked a non-inherited, de novo mutation in the dopamine transporter to autism spectrum disorder (ASD).
The research was partially funded by the MPSDC, and contributes to the overall objectives of the Transport Cycle in Neurotransmitter Uptake Systems project in which Mchaourab is an active collaborator.
The group’s research was published in the journal Molecular Psychiatry, with Mchaourab as one of the senior authors. You can read more about the publication here.
Read the Vanderbilt University Medical Center Reporter after the jump.
Read more »
Heiner Matthies, Ph.D., at the white board, leads a “seminar” for colleagues who hold vials of their fruit fly model that for the first time linked a non-inherited mutation in the dopamine transporter to autism. Seated at right, from the back, are Nicholas Campbell, Aurelio Galli, Ph.D., and P.J. Hamilton. Seated at left are Hassane Mchaourab, Ph.D., and James Sutcliffe, Ph.D. (photo by Susan Urmy)
With our 2013 annual meeting less than a month away, we are delighted to share with you the news about a new computational simulation technique developed by several MPSDC team members that was first presented at last year’s Frontiers in Membrane Protein Dynamics conference. The development of this technique speaks to the significant scientific collaborations that take place under the umbrella of the Consortium, as well as the scientific conversations that began in Chicago last year.
At the conference, Benoît Roux from our Computational Modeling Core introduced his team’s findings obtained from DEER (Double Electron-Electronic Resonance) data. At the conference, Roux and his team received helpful feedback from a number of scholars affiliated with the MPSDC as well as external invitees. After the conference, Roux and his team collaborated with a number of other scientists, including consortium colleague Hassane Mchaourab, to develop a novel computational simulation technique for exploiting the information from distance distribution data obtained from ESR/DEER spectroscopy for the refinement of membrane protein structures. This simulation technique, called the Restrained-Ensemble Molecular Dynamics (REMD) simulation method, uses a global ensemble-based energy restraint to force the spin-spin distance distribution histograms calculated from a multiple-copy molecular dynamics simulation to match those obtained from ESR/DEER experiments.
Already, the method has yielded three unique publications detailing the results of these experiments:
- Islam, S. M.; Stein, R.; Mchaourab, H.; Roux, B. Structural Refinement from Restrained-Ensemble Simulations Based on EPR/DEER Data: Application to T4 Lysozyme, J. Phys. Chem. B 117(17): 4740-54, 2013. (link)
- Roux, B.; Islam, S. M. Restrained-Ensemble Molecular Dynamics Simulations Based on Histograms from Double Electron-Electron Resonance Spectroscopy, J. Phys. Chem. B 117(17): 4733-9, 2013, In Press. (link)
- Roux, B.; Weare, J. On the statistical equivalence of restrained-ensemble simulations with the maximum entropy method, J. Chem. Phys. 138(8): 084107, 2013. (link)
The article co-authored by Benoît Roux and Jeane Weare was highlighted by the Journal of Chemical Physics on their Top 20 Most Read in March 2013.
Roux and his team have also gone on to apply this method to VSD (voltage-sensing domain) data with Eduardo Perozo, and Glt(Ph) data with Olga Boudker. Additionally, Wonpil Im is also implementing an easy setup of this method with dummy spin-labels on his CHARMM-GUI generator.
Shahidul M. Islam from Roux’s team, who co-authored two of the above papers and has been deeply involved in the scientific process, provided the MPSDC with an overview of the technique and its utility. We invite you to read his overview here »
Congratulations to all involved in the development of this exciting and important new method!
The Great Lakes Consortium for Petascale Computation has awarded access to the Blue Waters supercomputer — which is capable of performing quadrillions of calculations every second and of working with quadrillions of bytes of data — to 10 diverse science and engineering projects, including a project titled “The mechanism of the sarco/endoplasmic reticulum ATP-driven calcium pump”, spearheaded by Benoît Roux and his team.
Blue Waters supercomputer. Click to enlarge.
The Great Lakes Consortium for Petascale Computation is a collaboration among colleges, universities, national research laboratories, and other educational institutions that facilitates the widespread and effective use of petascale computing. The computing and data capabilities of Blue Waters will assist researchers in addressing questions of biology, nanoelectronics, ecological and economic impacts of climate change, and more.
Roux’s work with the Blue Waters supercomputer will make a significant contribution to the Conformational Transitions in P-class ATPases Project of the Membrane Protein Structural Dynamics Consortium (MPSDC), in which Roux collaborates with Francisco Bezanilla. Roux’s team provided the following description of their research plans with Blue Waters:
Maintaining optimum concentration gradients of monovalent (Na+, K+) and divalent (Ca2+) ions across cell membranes is a crucial part of signaling and regulation of many biological processes. Positively charged ions, being impermeable to largely hydrophobic cell membranes, need special passages to travel in and out of the living cell. Nature’s answer to this problem is two classes of membrane proteins called ion channels and ion pumps. Ion channels are responsible for the passive transport of selected ions, while ion pumps consume ATP to transport ions against their gradient.
Understanding the detailed molecular mechanism of ion pumps has been a long standing problem. In the early parts of the previous decade, a major breakthrough came in the form of determination of atomic resolution X-ray crystal structures of calcium transporting pump of sarcoplasmic reticulum of skeletal muscles (SERCA) that uses ATP hydrolysis as a source of free energy. Detailed structural studies of the pump under different conditions provided analogues of various intermediates in the reaction cycle and revealed important changes in the tertiary structure of the protein both in the cytoplasmic and in the transmembrane parts. Two major outstanding issues are the pathways of the ions to and from the transmembrane binding sites and a detailed understanding of the large scale conformational changes among various functionally relevant states. We will apply all-atom molecular dynamics (MD) and string method with swarms-of-trajectories to study transition pathways among various experimental structures.
The allocations provided on the Blue Waters supercomputer will allow us to study this important membrane protein with unprecedented detail. This study will reveal the molecular mechanism of an important step in the ion pumping process of a P-type ATPase and will provide a solid ground to understand other ATP-driven ion pumps such as the sodium-potassium pump, which shares very high sequence similarity with SERCA. ”
Congratulations to Benoît and his team for receiving this important award!
Learn more about the Blue Waters supercomputer »