Vanderbilt University School of
MRBIII, Room 5144B
5144B BIOSCI/MRBIII Vanderbilt University 372332-8725
computational structural biology, protein design, ligand docking, protein structure elucidation, cheminformatics, chemical biology,Biochemistry,Membrane,Neuroscience,NMR,Protein Structure,Spectroscopy,Structural Biology
Computational and Experimental Structural and Chemical Biology
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: 1) to enable protein structure elucidation of membrane proteins ? the primary target of most therapeutics ? and large macromolecular complexes such as viruses; 2) design proteins with novel structure and/or function to explore novel approaches to protein therapeutics and deepen our understanding of protein folding pathways, and 3) 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. For a complete list of research projects please visit www.meilerlab.org. Current research projects include:
1) Protein Structure Elucidation of EMRE. EmrE is a 12 kDa small multidrug resistant transporter (SMR) protein. It contributes to multidrug resistance in cancer and bacterial cells by removing compounds toxic to the cell such as the therapeutics. EmrE has been shown to contain four transmembrane a-helices and form a homodimer. While X-Ray crystallography and NMR spectroscopy frequently yield datasets for membrane proteins that are of lesser quality and/or sparse compared to soluble proteins, extensive Electron Paramagnetic Resonance (EPR) and cryo-Electron Microscopy (cryo-EM) datasets are available for EmrE. We develop computer algorithms tailored for determining the structure from these low resolution/sparse experimental data with the ultimate goal of solving the structure of EmrE and other membrane proteins. By determining the structure of EmrE, novel chemotherapeutic agents could be developed, including those to combat multidrug resistance.
2) Design of Protein Antibiotics. Gram positive bacterial infections are a significant global cause of human mortality. More than 125,000 people contract multidrug-resistant gram positive infections annually in the U.S. alone, resulting in more than 40,000 deaths per year. Vancomycin is the last-line antibiotic for gram-positive infections. It kills bacteria by binding the -D-ala-D-ala C-terminus of a key bacterial cell wall glycopeptide component, thereby inhibiting proper cell wall biosynthesis. The most common mechanism of acquired resistance is through the substitution of a -D-lac in place of the -D-ala at the C-terminus of the bacterial glycopeptide. The goal of this project is to explore a rational design approach to develop novel antimicrobial protein therapeutics capable of binding both the multidrug-resistant -D-ala-D-ala and vancomycin-resistant -D-ala-D-lac target peptides.
3) Novel Schizophrenia Therapeutics by Virtual High-Throughput Screening. Selective potentiators of the metabotropic glutamate receptor subtype mGluR5 have exciting potential for development of novel treatment strategies for schizophrenia. A high-throughput screen (HTS) for mGluR5 potentiators at Vanderbilt?s molecular libraries screening center network facility revealed a large and diverse set of about 1,400 substances. We utilize the power of recent machine learning techniques such as Artificial Neural Networks (ANNs) and Support Vector Machines (SVMs) to model the complex relationship between chemical structure and biological activity of mGluR5 potentiators. These models will be used to virtually screen millions of compounds for activity and guide chemical synthesis of novel compounds.
Lemmon, G, Kaufmann, K, Meiler, J. Prediction of HIV-1 protease/inhibitor affinity using RosettaLigand. Chem Biol Drug Des, 79(6), 888-96, 2012. PMCID:3351742
Lemmon, G, Meiler, J. Rosetta Ligand docking with flexible XML protocols. Methods Mol Biol, 819, 143-55, 2012. PMCID:3351742
Lindert, S, Alexander, N, W??tzel, N, Karaka??, M, Stewart, PL, Meiler, J. EM-fold: de novo atomic-detail protein structure determination from medium-resolution density maps. Structure, 20(3), 464-78, 2012. PMCID:3351742
Lindert, S, Alexander, N, W??tzel, N, Karaka??, M, Stewart, PL, Meiler, J. Ab initio protein modeling into CryoEM density maps using EM-Fold. Biopolymers, 97(9), 669-77, 2012. PMCID:3351742
Mueller, R, Dawson, ES, Meiler, J, Rodriguez, AL, Chauder, BA, Bates, BS, Felts, AS, Lamb, JP, Menon, UN, Jadhav, SB, Kane, AS, Jones, CK, Gregory, KJ, Niswender, CM, Conn, PJ, Olsen, CM, Winder, DG, Emmitte, KA, Lindsley, CW. Discovery of 2-(2-benzoxazoyl amino)-4-aryl-5-cyanopyrimidine as negative allosteric modulators (NAMs) of metabotropic glutamate receptora??5 (mGlua??): from an artificial neural network virtual screen to an in vivo tool compound. ChemMedChem, 7(3), 406-14, 2012. PMCID:3351742
Mueller, R, Dawson, ES, Niswender, CM, Butkiewicz, M, Hopkins, CR, Weaver, CD, Lindsley, CW, Conn, PJ, Meiler, J. Iterative experimental and virtual high-throughput screening identifies metabotropic glutamate receptor subtype 4 positive allosteric modulators. J Mol Model, , , 2012.
Yang, R, Shi, J, Byeon, IJ, Ahn, J, Sheehan, JH, Meiler, J, Gronenborn, AM, Aiken, C. Second-site suppressors of HIV-1 capsid mutations: restoration of intracellular activities without correction of intrinsic capsid stability defects. Retrovirology, 9, 30, 2012. PMCID:3351742
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. Mol Pharmacol, 79(1), 42-50, 2011. PMCID:3014278
DeLuca, S, Dorr, B, Meiler, J. Design of native-like proteins through an exposure-dependent environment potential. Biochemistry, 50(40), 8521-8, 2011. PMCID:3351742
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. J Am Chem Soc, 133(45), 18026-9, 2011. PMCID:3351742
Ganguly, S, Weiner, BE, Meiler, J. Membrane protein structure determination using paramagnetic tags. Structure, 19(4), 441-3, 2011. PMCID:3351742
Gregory, KJ, Dong, EN, Meiler, J, Conn, PJ. Allosteric modulation of metabotropic glutamate receptors: structural insights and therapeutic potential. Neuropharmacology, 60(1), 66-81, 2011. PMCID:2981682
Henry, LK, Iwamoto, H, Field, JR, Kaufmann, K, Dawson, ES, Jacobs, MT, Adams, C, Felts, B, Zdravkovic, I, Armstrong, V, Combs, S, Solis, E, Rudnick, G, Noskov, SY, DeFelice, LJ, Meiler, J, Blakely, RD. A conserved asparagine residue in transmembrane segment 1 (TM1) of serotonin transporter dictates chloride-coupled neurotransmitter transport. J Biol Chem, 286(35), 30823-36, 2011. PMCID:3351742
Hirst, SJ, Alexander, N, McHaourab, HS, Meiler, J. RosettaEPR: an integrated tool for protein structure determination from sparse EPR data. J Struct Biol, 173(3), 506-14, 2011. PMCID:3040274
Kazmier, K, Alexander, NS, Meiler, J, McHaourab, HS. Algorithm for selection of optimized EPR distance restraints for de novo protein structure determination. J Struct Biol, 173(3), 549-57, 2011. PMCID:3073550
Koehler, J, Meiler, J. Expanding the utility of NMR restraints with paramagnetic compounds: background and practical aspects. Prog Nucl Magn Reson Spectrosc, 59(4), 360-89, 2011. PMCID:3351742
Morin, A, Kaufmann, KW, Fortenberry, C, Harp, JM, Mizoue, LS, Meiler, J. Computational design of an endo-1,4-beta-xylanase ligand binding site. Protein Eng Des Sel, 24(6), 503-16, 2011. PMCID:3092692
Morin, A, Meiler, J, Mizoue, LS. Computational design of protein-ligand interfaces: potential in therapeutic development. Trends Biotechnol, 29(4), 159-66, 2011. PMCID:3092692
Woetzel, N, Lindert, S, Stewart, PL, Meiler, J. BCL::EM-Fit: rigid body fitting of atomic structures into density maps using geometric hashing and real space refinement. J Struct Biol, 175(3), 264-76, 2011. PMCID:3351742
Lowe, EW, Ferrebee, A, Rodriguez, AL, Conn, PJ, Meiler, J. 3D-QSAR CoMFA study of benzoxazepine derivatives as mGluR5 positive allosteric modulators. Bioorg Med Chem Lett, 20(19), 5922-4, 2010. PMCID:2943337
Alexander, N, Bortolus, M, Al-Mestarihi, A, Mchaourab, H, Meiler, J. De novo high-resolution protein structure determination from sparse spin-labeling EPR data. Structure, 16(2), 181-95, 2008. PMCID:2390841
Henry, LK, Meiler, J, Blakely, RD. Bound to be different: neurotransmitter transporters meet their bacterial cousins. Mol Interv, 7(6), 306-9, 2007.
Reese, M, S?!nchez-Pedregal, VM, Kubicek, K, Meiler, J, Blommers, MJ, Griesinger, C, Carlomagno, T. Structural Basis of the Activity of the Microtubule-Stabilizing Agent Epothilone
A Studied by NMR Spectroscopy in Solution. Angew Chem Int Ed Engl, 46(11), 1864-1868, 2007.
Smith, JA, Vanoye, CG, George, AL, Meiler, J, Sanders, CR. Structural models for the KCNQ1 voltage-gated potassium channel. Biochemistry, 46(49), 14141-52, 2007. PMCID:2565492
Lakomek, NA, Carlomagno, T, Becker, S, Griesinger, C, Meiler, J. A thorough dynamic interpretation of residual dipolar couplings in ubiquitin. J Biomol NMR, 34(2), 101-15, 2006.
Meiler, J, Baker, D. ROSETTALIGAND: protein-small molecule docking with full side-chain flexibility. Proteins, 65(3), 538-48, 2006.
S?!nchez-Pedregal, VM, Kubicek, K, Meiler, J, Lyothier, I, Paterson, I, Carlomagno, T. The tubulin-bound conformation of discodermolide derived by NMR studies in
solution supports a common pharmacophore model for epothilone and discodermolide. Angew Chem Int Ed Engl, 45(44), 7388-94, 2006.
Zanghellini, A, Jiang, L, Wollacott, AM, Cheng, G, Meiler, J, Althoff, EA, R??thlisberger, D, Baker, D. New algorithms and an in silico benchmark for computational enzyme design. Protein Sci, 15(12), 2785-94, 2006. PMCID:2242439
Bradley, P, Malmstr??m, L, Qian, B, Schonbrun, J, Chivian, D, Kim, DE, Meiler, J, Misura, KM, Baker, D. Free modeling with Rosetta in CASP6. Proteins, 61 Suppl 7, 128-34, 2005.
Gra??a, O, Baker, D, MacCallum, RM, Meiler, J, Punta, M, Rost, B, Tress, ML, Valencia, A. CASP6 assessment of contact prediction. Proteins, 61 Suppl 7, 214-24, 2005.
Lakomek, NA, Far??s, C, Becker, S, Carlomagno, T, Meiler, J, Griesinger, C. Side-chain orientation and hydrogen-bonding imprint supra-tauc motion on the
protein backbone of ubiquitin. Angew Chem Int Ed Engl, 44(47), 7776-8, 2005.
Meiler, J, Baker, D. The fumarate sensor DcuS: progress in rapid protein fold elucidation by combining
protein structure prediction methods with NMR spectroscopy. J Magn Reson, 173(2), 310-6, 2005.
S?!nchez-Pedregal, VM, Reese, M, Meiler, J, Blommers, MJ, Griesinger, C, Carlomagno, T. The INPHARMA method: protein-mediated interligand NOEs for pharmacophore mapping. Angew Chem Int Ed Engl, 44(27), 4172-5, 2005.
Griesinger, C, Peti, W, Meiler, J, Br??schweiler, R. Projection angle restraints for studying structure and dynamics of biomolecules. Methods Mol Biol, 278, 107-21, 2004.
Kuhn, M, Meiler, J, Baker, D. Strand-loop-strand motifs: prediction of hairpins and diverging turns in proteins. Proteins, 54(2), 282-8, 2004.
Meiler, J, K??ck, M. Novel methods of automated structure elucidation based on 13C NMR spectroscopy. Magn Reson Chem, 42(12), 1042-5, 2004.
Bradley, P, Chivian, D, Meiler, J, Misura, KM, Rohl, CA, Schief, WR, Wedemeyer, WJ, Schueler-Furman, O, Murphy, P, Schonbrun, J, Strauss, CE, Baker, D. Rosetta predictions in CASP5: successes, failures, and prospects for complete
automation. Proteins, 53 Suppl 6, 457-68, 2003.
Carlomagno, T, Blommers, MJ, Meiler, J, Jahnke, W, Schupp, T, Petersen, F, Schinzer, D, Altmann, KH, Griesinger, C. The high-resolution solution structure of epothilone A bound to tubulin: an
understanding of the structure-activity relationships for a powerful class of antitumor agents. Angew Chem Int Ed Engl, 42(22), 2511-5, 2003.
Meiler, J. PROSHIFT: protein chemical shift prediction using artificial neural networks. J Biomol NMR, 26(1), 25-37, 2003.
Meiler, J, Baker, D. Coupled prediction of protein secondary and tertiary structure. Proc Natl Acad Sci U S A, 100(21), 12105-10, 2003. PMCID:218720
Meiler, J, Baker, D. Rapid protein fold determination using unassigned NMR data. Proc Natl Acad Sci U S A, 100(26), 15404-9, 2003. PMCID:307580
Meiler, J, Peti, W, Griesinger, C. Dipolar couplings in multiple alignments suggest alpha helical motion in ubiquitin. J Am Chem Soc, 125(27), 8072-3, 2003.
Hutter, MC, Krebs, J, Meiler, J, Griesinger, C, Carafoli, E, Helms, V. A structural model of the complex formed by phospholamban and the calcium pump
of sarcoplasmic reticulum obtained by molecular mechanics. Chembiochem, 3(12), 1200-8, 2002.
Meiler, J, Maier, W, Will, M, Meusinger, R. Using neural networks for (13)c NMR chemical shift prediction-comparison with
traditional methods. J Magn Reson, 157(2), 242-52, 2002.
Meiler, J, Sanli, E, Junker, J, Meusinger, R, Lindel, T, Will, M, Maier, W, K??ck, M. Validation of structural proposals by substructure analysis and 13C NMR chemical
shift prediction. J Chem Inf Comput Sci, 42(2), 241-8, 2002.
Meiler, J, Will, M. Genius: a genetic algorithm for automated structure elucidation from 13C NMR
spectra. J Am Chem Soc, 124(9), 1868-70, 2002.
Peti, W, Meiler, J, Br??schweiler, R, Griesinger, C. Model-free analysis of protein backbone motion from residual dipolar couplings. J Am Chem Soc, 124(20), 5822-33, 2002.
Carlomagno, T, Blommers, MJ, Meiler, J, Cuenoud, B, Griesinger, C. Determination of aliphatic side-chain conformation using cross-correlated relaxation:
application to an extraordinarily stable 2''-aminoethoxy-modified oligonucleotide triplex. J Am Chem Soc, 123(30), 7364-70, 2001.
Meiler, J, Prompers, JJ, Peti, W, Griesinger, C, Br??schweiler, R. Model-free approach to the dynamic interpretation of residual dipolar couplings
in globular proteins. J Am Chem Soc, 123(25), 6098-107, 2001.
Meiler, J, Will, M. Automated structure elucidation of organic molecules from (13)c NMR spectra
using genetic algorithms and neural networks. J Chem Inf Comput Sci, 41(6), 1535-46, 2001.
Meiler, J, Blomberg, N, Nilges, M, Griesinger, C. A new approach for applying residual dipolar couplings as restraints in structure
elucidation. J Biomol NMR, 16(3), 245-52, 2000.
Meiler, J, Meusinger, R, Will, M. Fast determination of 13C NMR chemical shifts using artificial neural networks. J Chem Inf Comput Sci, 40(5), 1169-76, 2000.
Meiler, J, Peti, W, Griesinger, C. DipoCoup: A versatile program for 3D-structure homology comparison based on
residual dipolar couplings and pseudocontact shifts. J Biomol NMR, 17(4), 283-94, 2000.
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