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Meiler Lab Computational Chemical and Structural Biology |
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Meiler Lab 2010
The Bio Chemical Library (BCL) is a software package that provides unique tools for biological research, such as protein structure determination from sparse experimental data. The BCL contains the widely used secondary structure prediction program JUFO, a folding algorithm that assembles secondary structure elements, and loop construction tools that complete protein backbones. With this series of protocols the BCL allows construction of backbone models for large and membrane proteins from the more...
Despite improvements on both experimental techniques and computational prediction methods for small and medium sized proteins, structure elucidation and prediction for larger proteins remains a major challenge. We are developing a structure prediction algorithm that incorporates data of various experimental techniques but also to be used as a standalone tool. The algorithm utilizes a novel sampling technique and employs the flexible combination of empirical and experimental scores.The pro more...
A growing technique in protein structure determination is cryo-electron microscopy. Cryo-EM provides low resolution electron density maps ( ~8 Angstroem) . As this data become more accurate and you can use this data not only to determine the overall structure of protein complexes, but also to determine secondary structure elements and their assembly in the tertiary structure of a protein. The successful field of ab initio protein structure prediction can help to more...
Antibody structural repertoires are determined through diversity of gene segment usage and the introduction of somatic mutations. This structural diversity is responsible for the recognition of an unlimited number of antigens. Traditional techniques for determining structure cannot characterize the breath of structural diversity that these antibody-antigen interactions can adopt because of limited throughput. Using the knowledge-based structural biology program Rosetta, we can use the results from c more...
About 30% of the proteins in the human body are membrane proteins. They have a wide variety of functions within the cell and it is therefore not surprising that over half of all known drugs target them. However, less than 1% of the structures deposited in the ProteinDataBank belong to membrane proteins. The reason for this discrepancy is the difficulty to crystallize them. Also conventional liquid-state NMR techniques reach their limits for membrane proteins more...
A first step towards protein tertiary structure prediction is the identification of secondary structure elements from the sequence. In addition, the identification of trans-membrane spans is required for membrane proteins.
The aim of this project is to simultaneously predict secondary structure and trans-membrane spans with a single tool. The rationale for this approach is the hypothesis that both phenomena are interrelated: more...
Small molecule design consists of assembly, docking, and scoring. Since Rosetta already has a docking algorithm (RosettaLigand) and a scoring framework, all that is needed for small molecule design is an assembly algorithm. As an initial approach, we have chosen random assembly of fragments from an input library. The algorithm is represented in figure 1. Each cycle of design consists of extending the small molecule with random fragments chosen from a library, filtering small molecule designs based on energ more...
Learning systems have a long history in being applied to reduce the search space for protein structure prediction e.g. artificial neural networks (ANN) and hidden markov models (HMM) are used for protein secondary structure prediction and motif recognition. Recently, ANNs were successfully utilized to derive a consensus amino acid contact prediction for unknown folds from fold recognition techniques. These predictions drive de novo prediction of protein tertiary structure towards better r more...
Electron paramagnetic resonance (EPR) can provide structural information on proteins not easily studied by other biophysical techniques such as nuclear magnetic resonance and X-ray crystallography. Inter-residue distances of up to 60Å and residue specific solvent exposure can be measured. Such data can be critical to defining the topology of a protein. However, the amount of information obtained from an EPR dataset is limited by its sparseness and difficulty in r more...
Using cryo-electron microscopy (cryoEM) numerous sub-nanometer resolution density maps of large macromolecular assemblies have been recently reported. Although no atomic detail is generally resolved in these density maps, at 7 Å resolution α-helices are observed as density rods. The Primary goal of this project is the development of a computational protein structure prediction algorithm that incorporates the experimental cryoEM density map as restraints. The placemen more...
HIV protease inhibitors (PIs) have been an important and successful model for structure-assisted drug design. At least ten PIs have been approved by the FDA since 1995. However because of HIV-1’s high mutation rate, PI therapies often succumb to drug resistance mutations. Computational methods that predict how a putative inhibitor will interact with various strains of HIV-1 protease will speed the development of new inhibitors that avoid resistance mutation. HIV-1 protease mutants more...
Six of the ten most frequent protein topologies have symmetry on the fold level. We postulate that the evolutionary origin of these symmetric superfolds lies in naturally occurring homo-oligomeric protein complexes that undergo gene duplication and fusion. To test this hypothesis the Rosetta protein design package was used to computationally design a two-fold symmetric variant of imidazole glycerol phosphate synthase (HisF). The new protein, termed FLR, adopts the symmetric (??)8 TIM-barrel superfold. The more...
About Meiler Lab
Research in our laboratory seeks to fuse computational and experimental efforts to investigate proteins, the fundamental molecules of biology, and their interactions with small molecule substrates, therapeutics, or probes. We develop computational methods with three major ambitions in mind.
A) To enable protein structure elucidation of membrane proteins the primary target of most therapeutics and large macromolecular complexes such as viruses;
B) Design proteins with novel structure and/or function to explore novel approaches to protein therapeutics and deepen our understanding of protein folding pathways.
C) Understand the relation between chemical structure and biological activity quantitatively in order to design more efficient and more specific drugs.
Crucial for our success is the experimental validation of our computational approaches which we pursue in our laboratory or in collaboration with other scientists.
Current research applications focus on new approaches to a) drug and probe development for neurodegenerative disorders and diseases including Schizophrenia, Alzheimer's, and Parkinson's, b) understanding the structural determinants of antidepressant binding to neurotransmitter transporters, c) cardiac arrhythmia as caused by the complex interplay of potassium channel regulation and drug interactions, d) multidrug resistance in cancer and bacterial cells related to multidrug transporter proteins, and e) structural basis of viral infections and antibody activity.
News
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Jordan Willis was invited to give an oral presentation at the Keystone Symposia on HIV Vaccines
Sam Deluca wins fellowship from Phrma foundation!
Sam DeLuca, graduate student in the Meiler laboratory, wins an "Informatics" graduate student fellowship from the Phrma foundation. Sam's research focuses on computational modeling of protein-small molecule interactions for drug discovery.
Brittany Allison receives NSF fellowship!
Brittany Allison, a chemistry student in the Meiler laboratory, received a prestigious National Science Foundation (NSF) Graduate Research Fellowship. Brittany works on computationally engineering proteins that bind small molecules. Her research has implications for understanding the fundamentals of protein-ligand interaction, engineering enzymes, and protein therapeutics. Brittany will start her fellowship after completing her training on the Chemical Biology Training Program, an NIH-funded initiative of Vanderbilt's Institute for Chemical Biology and the Chemistry Department.
Congrats to Sandeep Kothiwale for passing prequalifying exams
Sandeep presented his research plan entitled "Enhancement of drug discovery tools through knowledge based conformational sampling and chemical shift predictions"
Congrats to Daniel Putnam: 2nd place Finalist in AMIA Student Paper Competition!
Daniel Putnam's AMIA paper - "Exploring Schizophrenia Drug-Gene Interactions Through Molecular Network and Pathway Modeling", has been accepted as one of the eight finalists in the Student Paper Competition at the American Medical Informatics Association conference in October. Update 10/28/2011: Daniel was awarded 2nd place at the conference, congratulations, Daniel!
Congratulations Dr. Woetzel!
Nils Woetzel successfully defended his thesis, “A novel approach to de novo protein structure prediction using knowledge based energy functions and experimental restraints."
Zollie White receives Top Prize at the 2011 Herty Medalist Undergraduate Research Symposium
Zollie White, an undergrad from Morehouse College, spent the summer of 2011 researching with Will Lowe in the Meiler Lab through the Vanderbilt REU program. He presented this research at the 2011 Herty Medalist Undergraduate Research Symposium held at Morehouse College was awarded the top prize. For this, he received a one-year membership to the American Chemical Society (ACS) and a $500 travel award to a national ACS conference. Congrats, Zollie!
Congratulations Dr. Karakas!
Congrations to Mert Karakas for having successfully defended his thesis "BCL::Fold-De novo Protein Structure Prediction by Assembly of Secondary Structure Elements"
Salisbury, David. "Creation of the largest human-design protein boosts protein engineering efforts." Vanderbilt Reporter, Nov 2011.
Synder, B. "School for Science and Math student sees paper published." VUMC Reporter, Vol XXI, 34. Sep 2011.
Snyder, B. "Study shows how G proteins get "turned on" by receptors" Vanderbilt Reporter 2011.
Baynham, D. Q.; Karakas, M.; Meiler, J. "Protein Structure Prediction Using Rosetta" Young Scientist, May 2011, p11-12
Smith, S. "As Beckman Scholars, undergraduates experience responsibility and research life" Arts & Science, Vanderbilt University, Spring 2011
Schreiber, A.; Meiler, J. "Modellierung G-Protein-gekoppelter Rezeptoren mit ROSETTA " Biospektrum
Joetten, F. "Formvollendet" Bild der Wissenschaft 2010, 4, 18-23.
Omlor, A.; Meiler, J. "Zu Gast im Meiler Lab an der Vanderbilt University in Nashville Tennessee!"
Jaehnigen, S.; Grjasnow, A.; Meiler, J. "Chemische und strukturelle Biologie waehrend eines Praktikum in den USA" Faszination Chemie 2009, 14., p12-16
Marino, M. "Undergraduate Open House" Vanderbilt Reporter 2008, 4.
Lerner, M. "Europe's Brain Drain" European Hospital 2008, 17, 4.
Marino, M. "Program promotes greater diversity in molecular sciences" Vanderbilt Reporter 2007, 3.
Salisbury, D. F. "Campus 'supercomputer' helps decipher mysteries of science" Vanderbilt Register 2
Joetten, F. "Ich, der Roboter" Die Zeit 2007, 41, 42-43.
Meiler, J. "Kuenstliche Intelligenz in Chemie und Biologie" Faszination Chemie 2001, 7, 35-43.
Interaction of a G protein with an activated receptor opens the interdomain interface in the alpha subunit (2011) PNAS
Andrew Morin;Jens Meiler, Laura Mizoue
Computational design of protein-ligand interfaces: Potential in Therapeutic Development. (2011) Trends in Biotechnology
Fortenberry C;Bowman EA, Proffitt W, Dorr B, Combs S, Harp J, Mizoue L, Meiler J
Exploring Symmetry as an Avenue to the Computational Design of Large Protein Domains (2011) J. Am. Chem. Soc.
Soumya Ganguly;Brian E. Weiner, Jens Meiler
Membrane Protein Structure Determination using Paramagnetic Tags (2011) Structure
Olmsted IR;Xiao Y, Cho M, Csordas AT, Sheehan JH, Meiler J, Soh HT, Bornhop DJ.
Measurement of Aptamer-Protein Interactions with Back-Scattering Interferometry (2011) Analytical Chemistry
Keith Henry;Hideki Iwamoto, Julie R. Field, Kristian Kaufmann, Eric S. Dawson, Miriam T. Jacobs, Chelsea Adams, Bruce Felts, Igor Zdravkovic, Vanessa Armstrong, Steven Combs, Ernesto Solis, Gary Rudnick, Sergei Y. Noskov, Louis J. DeFelice, Jens Meiler, and Randy D. Blakely
A Conserved Asparagine Residue in Transmembrane Segment 1 (TM1) of Serotonin Transporter Dictates Chloride-coupled Neurotransmitter Transport (2011) Journal of Biological Chemistry
Julia Koehler;Jens Meiler
Expanding the utility of NMR restraints with paramagnetic compounds: Background and practical aspects (2011) Progress in Nuclear Magnetic Resonance Spectroscopy
Bhave G;Chauder BA, Liu W, Dawson ES, Kadakia R, Nguyen TT, Lewis LM, Meiler J, Weaver CD, Satlin LM, Lindsley CW, Denton JS
Development of a selective small-molecule inhibitor of Kir1.1, the renal outer medullary potassium channel (2011) Molecular Pharmacology
Will Lowe received an NSF fellowship for his project "PROPMAP: A Novel GPU-accelerated Structure-Property Relationship Mapping Algorithm Utilizing Volunteer Computing." The prestigious award supports Dr. Lowe's research for three years in the Meiler Lab. Congrats, Will!
Liz Dong Receives DAAD Award
Liz Dong of the Jens Meiler lab at Vanderbilt recently received a short term research grant to study at the Univeristy of Leipzig in Leipzig, Germany. She will spend one month this fall developing a computational method that will allow for the binding pose of a drug within a receptor to be determined. Her method will be guided by experimental data collected on drugs that bind G-protein coupled receptors, working with the lab of Torsten Schöneberg. Congrats, Liz!
Mariusz passes his qualifying exam!
Mariusz passed his qualifying exam with his proposal: Comprehensive protein-ligand interaction mapping through quantitative structure activity relationships. Congratulations Mariusz!
Joe Crivelli's cancer research project in the Meiler lab covered in Vanderbilt's Arts and Sciences magazine!
http://www.vanderbilt.edu/magazines/arts-and-science/2011-05/in-the-lab-early
Meiler lab undergraduate Zachary Glaser received early acceptance into VU Medical School
Congratulations Zach!
Kelli Kazmier awarded a doctoral fellowship
Kelli's was awarded an NIH NRSA doctoral fellowship to investigate "Conformational Changes Underlying Intracellular Gating of the Leucine
Transporter." Congratulations Kelli!
Sten passes his qualifying exam!
Sten passed his qualifying exam with his proposal: A novel approach
to de novo protein structure prediction using multiple partial templates. Congratulations Sten!
Ralf Mueller earns his PhD!
Ralf successfully defended his thesis, Machine Learning Algorithms for Prediction of Biological Activity and Chemical Properties, earning his PhD, Congratulations Ralf!
Congratulations to Dr. Jens Meiler
Dr. Jens Meiler was promoted to Associate Professor with tenure.
Andrew Morin's Successful Ph.D. Defense
Congratulations to Andrew Morin on successfully defending his PhD thesis on April 26, 2011. The thesis was presented on "The Computaional Design of Protein Ligand Interfaces".
Congratulations to Steven Combs !!!
Steven Combs has successfully passed his qualifying exam on April 23, 2011 and proposed his research on "Thermostabilization of industrially relevant proteins through computational design of partial covalent interactions".
Grant awarded from Vanderbilt University Discovery Grant.
Meiler Laboratory has been awarded Vanderbilt University Discovery Grant for research on "De novo Design of Large protein".
Best Oral Presentation at CPB retreat from Meiler Lab
Liz Dong has won best oral presentation prize at Chemical & Physical Biology retreat at Nashville Zoo on April 18, 2011. She gave her oral presentation on "Structural studies of the interaction between mDlu5 and allosteric modulator". Congratulations to Liz !!!
Julia Koehler Won Travel Grant!!
Julia Koehler won a travel grant to attend the Gordon Research Conference "Computational Aspects - Biomolecular NMR" in May 2011 and will present her work on " De novo membrane protein folding from sparse NMR data ". Congratulations!!!
Brittany's Preliminary Qualification Exam
Brittany Allison, a graduate student at Meiler Lab has successfully passed her Priliminary Qualification Exam on April 6, 2011.
Summer Student from Meiler Lab Won Goldwater Fellowship
Louesa Akin is a undergraduate student attending Centre College in Kentucky who pursues research in the Meiler laboratory focused on Membrane Protein Structure Prediction using sparse NMR restraints. She was selected to receive the Goldwater Scholarship for undergraduate students. Louesa participated in the Summer Science Academy program in summer 2010 and will participate in the Research Experience for Undergraduates in chemical biology in summer 2011.
Congratulations to Elizabeth Dong!!!
Liz Dong is a MD/PhD student in the second year of her graduate studies. She won the prestigious PhRMA-Paul Calabresi Medical Student Research Fellowship. The fellowship is offered to medical students who have substantial interests in research and teaching careers in pharmacology - clinical pharmacology. Liz works on new technologies in the Meiler laboratory to develop allosteric modulators of metabotropic glutamate receptors, important targets for many neurological diseases.
David Nannemann - Dissertation Defense on March 25th 2011
David Nannemann will be defending his Doctoral research on "Directed Biosynthesis of the Nucleoside Analog Drug Didanosine", at the Stevenson Center, Room 5502, 2:00 pm.
Stephanie Hirst successfully passed her Qualifying Exam
Stephanie Hirst unconditionally passed her Qualifying Exam on February 3, 2011 and the proposal was called "Structural Elucidation of the Role of Na+ and Leucine Binding in the LeuT Transport Mechanism using ROSETTAEPR". Congratulations to Stephanie!!!
Steffen Lindert successfully defends his research dissertation
Steffen presented his doctoral research dissertation “CryoEM guided de-novo protein folding” on November 22nd, 2010. His thesis committee approved his presentation and accepted his research, making him the first to complete the Chemical and Physical Biology PhD Program. Congratulations, Steffen!!
Meiler Lab member Steffen Lindert receives NIH travel award to give a presentation in Hawaii.
Steffen Lindert will give a presentation at the Pacific Symposium on Biocomputing in January on Hawaii (about EM-Fold and our results participating in the cryoEM modeling challenge). He received an NIH travel award to cover the costs associated with the conference.
Liz Dong successfully passed her Qualifying Exam in September
Congratulations to Liz Dong, an MD/PhD student in the Meiler lab, on her successful completion of qualifying exams on 9/2/2010
Meiler Lab Publication Makes the List of Top 20 Most Downloaded Biochemistry Articles!
Congratulations to Meiler Lab members Kristian W. Kaufmann, Gordon H. Lemmon, Samuel L. DeLuca, and CSB outreach coordinator, Jonathan H. Sheehan! Their recent publication, "Practically Useful: What the Rosetta Protein Modeling Suite Can Do for You" made the list of the TOP 20 most downloaded articles from the journal Biochemistry.