William J. Wedemeyer
The Wedemeyer lab combines computational and experimental methods to answer important biological questions about protein structure. Our principal focus is gp120 (the envelope protein of HIV) but we are also pursuing basic research about the physics of protein folding using peptides and small proteins. Our software is protected by the GNU Public License.
Conformational Changes in gp120 During HIV-1 Cell Entry
HIV is perhaps the most critical public health problem of our time, with roughly 40 million people infected and roughly 10,000 deaths per day. The HIV envelope protein, gp120, is the principal target for vaccines and antibody neutralization, being the sole exposed viral protein. However, gp120-based vaccines have not been successful and relatively few anti-gp120 antibodies are effective at neutralizing the virus; of these few antibodies, none are effective against all forms of the virus. MORE
Computational Protein Structure Prediction/Design
The methods of computational protein structure prediction have matured in recent years, so that the structure of individual domains can be predicted de novo (i.e., from the amino-acid sequence alone) within 3-5 Å CA rmsd. Nevertheless, these methods are prone to fail if the domain is unusually large (>150 residues), has poorly predicted secondary structure, or has a high fraction of long-range contacts. Moreover, there are no reliable methods for refining approximately correct structures (e.g., 5 Å CA rmsd to native) to higher resolution (e.g., 3 Å CA rmsd). We are developing new sampling methods and force-fields to overcome these obstacles.
Experimental Studies of Protein/Peptide Electrostatics
Successful protein prediction and design requires accurate energy functions for scoring trial conformations. Unfortunately, the electrostatic component of present-day energy functions seems to be inaccurate; this is especially problematic, since the electrostatic component is long-ranged. We are studying the electrostatics of peptides and proteins experimentally in an effort to improve these potential functions.
VA Voelz, VR Singh, WJ Wedemeyer, LJ Lapidus, VS Pande. 2010. Unfolded-State Dynamics and Structure of Protein L Characterized by Simulation and Experiment. J. Amer. Chem. Soc. 132 4702-4709.
Raghunathan K, Vago FS, Ball T, Yakubova N, Grindem D, Wedemeyer WJ, Arvidson DN. 2009. Expression, purification, crystallization and preliminary X-ray studies of Vibrio cholerae pseudopilin EpsH. Acta Crystallogr Sect F Struct Biol Cryst Commun. 1;65(Pt 7):702-4.
Waldauer SA, Bakajin O, Ball T, Chen Y, Decamp SJ, Kopka M, Jäger M, Singh VR, Wedemeyer WJ, Weiss S, Yao S, Lapidus LJ. 2008. Ruggedness in the folding landscape of protein L. HFSP J. 2(6):388-95.
Singh VR, Kopka M, Chen Y, Wedemeyer WJ, Lapidus LJ. 2007. Dynamic similarity of the unfolded states of proteins L and G. Biochemistry. 4;46(35):10046-54.
Baker ML, Jiang W, Wedemeyer WJ, Rixon FJ, Baker D, Chiu W. 2006. Ab initio modeling of the herpesvirus VP26 core domain assessed by CryoEM density. PLoS Comput Biol. 27;2(10):e146.
Fyfe JC, Menotti-Raymond M, David VA, Brichta L, Schäffer AA, Agarwala R, Murphy WJ, Wedemeyer WJ, Gregory BL, Buzzell BG, Drummond MC, Wirth B, O'Brien SJ. 2006. An approximately 140-kb deletion associated with feline spinal muscular atrophy implies an essential LIX1 function for motor neuron survival. Genome Res. 16(9):1084-90.
Tilton GB, Wedemeyer WJ, Browse J, Ohlrogge J. 2006. Plant coenzyme A biosynthesis: characterization of two pantothenate kinases from Arabidopsis. Plant Mol Biol. 61(4-5):629-42.
Mata IF, Wedemeyer WJ, Farrer MJ, Taylor JP, Gallo KA. 2006. LRRK2 in Parkinson's disease: protein domains and functional insights. Trends Neurosci. 29(5):286-93.
Rohankhedkar MS, Mulrooney SB, Wedemeyer WJ, Hausinger RP. 2006. The AidB component of the Escherichia coli adaptive response to alkylating agents is a flavin-containing, DNA-binding protein. J Bacteriol. 188(1):223-30.
Li X, Hood RJ, Wedemeyer WJ, Watson JT. 2005. Characterization of peptide folding nuclei by hydrogen/deuterium exchange-mass spectrometry. Protein Sci. 14(7):1922-8.
Svensson HG, Wedemeyer WJ, Ekstrom JL, Callender DR, Kortemme T, Kim DE, Sjobring U, Baker D. 2004. Contributions of amino acid side chains to the kinetics and thermodynamics of the bivalent binding of protein L to Ig kappa light chain. Biochemistry. Mar 9;43(9):2445-57.
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. 2003. Rosetta predictions in CASP5: successes, failures, and prospects for complete automation. Proteins. 53 Suppl 6:457-68.
Wedemeyer WJ, Baker DA. 2003. Efficient Minimization of Angle-Dependent Potentials for Polypeptides in Internal Coordinates. Proteins: Struct. Funct. Genet. 53, 262-272.
Wedemeyer WJ, Welker E, Scheraga HA. 2002. Proline Cis-Trans Isomerization and Protein Folding. Biochemistry, 41, 14637-14644. MORE