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.
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.
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.”
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.
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.
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 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.
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)
All-atom force fields are mathematical objects constructed from simple analytical functions parameterized to approximate the Born-Oppenheimer potential energy surface and reproduce known experimental observables. Parameters for the all-atom additive non-polarizable potential functions are currently available for amino acids, nucleic acids and common phospholipids. But accurate potential functions are also required for a growing number of novel molecules. Benoît Roux’s group at the University of Chicago has developed this Force Field Server for automatically generating testing and validating the all-atom nonpolarizable force fields used in MD simulations based on quantum mechanical (QM) calculations.
This GAAMP gateway is developed to help XSEDE users in using GAAMP for automated force field parameterization, based on the power of XSEDE computing resources. Currently, the trestles.sdsc.edu interface is being utilized. An interface for Blacklight users will be ready soon as well.
For the third year in a row, the Membrane Protein Structural Dynamics Consortium (MPSDC) hosted a number of events in its home base of Chicago during the month of May, key among these its third annual meeting. Unlike last year’s Frontiers in Membrane Protein Structural Dynamics conference, this year’s annual meeting was closed to the public, although there are plans to host a second open attendance conference in the near future.
Core workshops and minisymposium
As in previous years, the MPSDC’s Computational Modeling Core hosted a membrane protein modeling workshop, and a mini-symposium concerning the latest advances in computational approaches to the study of membrane proteins. As before, the modeling workshop provided attendants with an overview of the use of the modeling dynamics and visualization software NAMD and VMD, and also featured Dr. Wonpil Im’s CHARMM-GUI Ligand Binder module. This year’s mini-symposium covered a number of topics including force field and atomic models, structural modeling with low-resolution data, and transition pathways. The minisymposium hosted a “keynote” lecture of sorts on 2D-IR Spectroscopy, held by Josh Carr from the University of Wisconson-Madison. We are pleased to present you with a recording of Carr’s lecture, titled Connecting Experiment and Simulation by Modeling the Protein Amide I Band.
This year, the Consortium’s Membrane Protein Expression/Purification Core held its first workshop as well. This workshop featured several Consortium collaborators such as Edith Buchinger from Goethe University, Stephen Pless and Lilie Leisle from the University of Iowa, and Andrzej Rajca from the University of Nebraska. Topics discussed at this workshop included cellular and cell-free production of membrane proteins, reconstitution, incorporation of unnatural amino acids, single antigen binder technologies, and chemistry of protein modification and nitroxide spin labels. Both workshops and minisymposium were well attended and productive, and we will continue to host such satellite events in the future.
The MPSDC’s annual meeting allows for Consortium PI’s to present on the latest advances in the respective cores and projects, and serves as a dedicated time and space for members to discuss their research and organically find ways to collaborate with colleagues. Moreover, it gives the executive arm of the MPSDC the opportunity to report on “the state of the Consortium.”
At this year’s annual meeting at the University of Chicago’s Gleacher Center, MPSDC director Eduardo Perozo highlighted the continual exchange of ideas within and dynamics of the Consortium itself. Focusing specifically on the activities of the past year’s accomplishments, Dr. Perozo discussed the rational and efficient consolidation of Core Facilities to their highest efficiency and optimal productivity in close collaboration with individual projects. For example, the Computational Modeling core is starting to provide a number of services and home-developed algorithms to the community at large, from quick force field parameterization of small molecules (and potential membrane protein ligands) to the conformational energetics biophysical probes, to important tools to the use and interpretation of long range distances and distance distributions from DEER experiments. Additionally, Dr. Perozo reported on the status of the Consortium’s unique bridging and pilot projects. Four of our bridging projects are currently in full swing, and one of the pilot projects has successfully transitioned to bridging project status. We have also incorporated two exciting new Pilot projects that bring new systems and new techniques to the Consortium.
Followed by Dr. Perozo’s framing discussion, the PI’s of each of the three cores and seven projects described the progress made and latest scientific findings in their respective teams, providing attendees with the opportunity to respond and provide helpful feedback. The cores are designed to act as “innovation incubators” and research support centers by providing service and expertise in these critical areas: Membrane protein expression, the establishment of chemical synthesis capabilities for probes and detergents, the generation of a variety of binders and other crystallization chaperones and other target binders and the development of common computational tools to interpret and integrate the wealth of experimental data. Each of these feed and interconnect with individual projects in a highly interactive way.
The Consortium’s projects are integrated as research efforts that tie together or enhance the contribution of the independent work and expertise of the participating investigator to the Consortium and expand the independent work in new directions. Ten talks in all, each of the PI’s of the MPSDC’s cores and projects presented on the very latest activities, which will soon be disseminated to the public in the form of publications and resources.
On the second day of the annual meeting, we featured presentations from a number of our associate members. Associate members are junior faculty members who are pursuing exciting and innovative research parallel to the Consortium’s mission, and have therefore been given access to the interactions and core resources of the Consortium in a budget-neutral way.
Several of our associate members have gone on to participate full-fledged in the Consortium’s activities, either by way of participating in existing projects (such as Wonpil Im with the Computational Modeling Core or Chris Ahern with the Membrane Protein Expression/Purification Core) or by starting new pilot projects. Both Olga Boudker and Ming Zhou started as associated members, and after presenting on their research at last year’s conference have gone on to spearhead new and promising pilot projects.
Along these lines, we invited several of our associate members to present talks, in order to foster further cross-pollination between our research and theirs. This year, Luis Cuello from Texas Tech University presented on inactiviation gating at the K+ channel selectivity filter, Katherine Henzler-Wildman from Washington University presented on the mechanism of multi drug efflux by EmrE, Jens Meiler from Vanderbilt University presented on membrane protein structure & dynamics from limited experimental data, and Robert Keenan from the University of Chicago gave a talk on tail-anchored membrane protein insertion at the ER. In addition to Andrzej Rajca who participated in the Membrane Protein Production core workshop and other associate members like Francis Valiyaveetil, all of them bring state of the art expertise in different areas such as synthetic chemistry and chemical biology, and are expected to actively participate in several of the Consortium’s activities.
In sum, we are thrilled to report that the Consortium is thriving, from both a strictly scientific stand point as well as in regards to our output to the community. We’d like to thank all who attended and partook in this year’s discussions, and look forward to seeing you next year!
Below are several photos of the annual meeting and satellite events. You can either browse through the photos here or visit the set on Flickr.
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 Dynamicsconference. 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)
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!
Proteins may undergo multiple conformational changes required for their function. One strategy used to estimate target site positions in unknown structural conformations involves single-pair resonance energy transfer (RET) distance measurements. However, interpretation of inter-residue distances is difficult when applied to 3D structural rearrangements, especially in homomeric systems. Probe diffusion further complicates this task by biasing measurements towards shorter distances. Lanthanide resonance energy transfer (LRET) is an ideal technique for simultaneously resolving multiple distances within a protein. Hyde et al. (2012) recently combined LRET with an ensemble of numerical methods to form the Symmetric Nano-Positioning System (SNPS), which allows accurate 3D positioning and inter-probe distance estimation in functional homomeric proteins.
SNPS determines the 3D position of lanthanide donors [satellites] attached to a target site (one per subunit), relative to a single fluorescent acceptor [antenna] placed in a static reference site, as illustrated in the above figure. The acceptor’s position and accessible volume can be modeled from its structure-based labeling site by several methods, including dihedral scan analysis. SNPS can be applied to all defined conformational states of the protein and with simultaneous functional recordings. Satellite-to-antenna distances are encoded in time-resolved LRET lifetime decays. SNPS directly fits a 3D geometric model of satellite positions to LRET lifetime measurements using an inverse trilateration-based curve fitting procedure. Global analysis implementation fits the geometric model to an ensemble of replicate measurements. Numerical and analytical tools are integrated to account for probe diffusion and evaluate the confidence region of fitted positions. SNPS is well-suited to estimate 3D conformational changes at the target site between defined conformational states. In its first application, SNPS was used to determine the position of a functional voltage-gated potassium channel’s voltage sensor in its three major conformations [H. Clark Hyde, Walter Sandtner, Ernesto Vargas, Alper T. Dagcan, Janice L. Robertson, Benoit Roux, Ana M. Correa, Francisco Bezanilla (2012), Structure 20(10): 1629-1640].
The SNPS Toolbox contains the following stand-alone programs that implement the SNPS method:
SNPS: Performs inverse trilateration-based curve fitting of LRET lifetime decays to estimate the 3D position of lanthanide donors [satellites] attached to a target site (one per subunit), relative to a single fluorescent acceptor [antenna] placed in a static reference site. An acceptor file must be supplied by the user that specifies the acceptor’s coordinates and accessible volume. SNPS can alternatively fit all donor-acceptor distances constrained such that donors must lie in a polygon (symmetric) geometry, without any knowledge of acceptor position. SNPS can also simulate LRET lifetime decays at a user-defined donor position and noise level to explore the relation between donor position and decay shape. LRET lifetime decays are expected to be sensitized emission measured by a photomultiplier tube in analog mode (Poisson noise). The user imports lifetime decay files (ASCII .txt) and an acceptor file (ASCII .txt or Matlab .mat). See the “Example Data” folder for examples of required formatting. Fits are accompanied by a comprehensive set of output figures and a solution file.
DecayAnalysis: Performs model-free curve fitting of multi-exponential decays to estimate time constants and amplitudes (up to 4 exponential components). It is intended for donor-only time constant analysis of LRET experiments, but can also be used for general exponential fitting. The donor-only time constant is a required parameter for the SNPS program. The user can place constraints on time constants and define a weights scheme appropriate for the measurement uncertainty (e.g., Poisson vs. Gaussian noise). A large set of measurements can be fit quickly with basic statistical analysis reported. The user imports lifetime decay files in ASCII (.txt) format. See the “Example Data” folder for examples of required formatting.
Installation: Clicking on the downloadable .exe file will directly launch the Matlab Component Runtime (MCR) installation process and extract the SNPS and DecayAnalysis applications. This is a one-time installation, after which both applications can be launched. Installation of the included MCR is required even if you currently have Matlab or other MCR versions installed. Regarding processing speed, CPU speed takes precedence over the number of cores. The extracted folder also contains an “Example Data” folder with example data from the publication: AgTx2[II]-D20C-BODIPY-FL-maleimide acceptor cloud and Shaker S4(4) LBT construct sensitized emission (SE) and donor-only (DO) lifetime decays. Fit progress and information is displayed in an accompanying DOS window. Output files are written to a subfolder of the imported data directory.
The software was developed and written by H. Clark Hyde from Francisco Bezanilla’s group at the University of Chicago. Please contact us with questions or suggestions using the comments form below.