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: