Different ways to depict a protein structure Wire diagram Ribbon diagram Ball & stick of featured area Blue: positive Red: negative Space filling: van der Waals Surface representation (GRASP image) Petsko G.A., Ringe, D., Protein Structure and Function 2004, figure 5-5, pg. 173. Primary Structure: Amino Acid Sequence • Enter Somethign Model of HIV protease http://mgl.scripps.edu/projects/tangible_models/movies Tertiary Structure: An Example of an All-Alpha Protein, Hemoglobin Subunit Rotated 90 Degrees Tertiary Structure: An Example of an All-Beta Protein, Flu Virus Neuraminidase 1) Rotate 90 Degrees Tertiary Structure: An Example of an Alpha/Beta Protein, Triose Phosphate Isomerase 1) Rotate 90 Degrees Tertiary Structure: An Example of an Alpha + Beta Protein, TATA Binding Protein 1) Rotate 90 Degrees From Tertiary to Quaternary Structure: Hemoglobin as an Example • Quaternary structure -- the relative arrangement of two or more individual polypeptide chains • Protein assemblies can contain one type of polypeptide (homo-oligomer) or multiple types (hetero-oligomer) • Example: Hemoglobin (oxygen carrier in blood) • Hemoglobin is a hetero-tetramer composed of two alpha subunits and two beta subunits Hemoglobin, Tertiary Structure Hemoglobin, Quaternary Structure Tetrameric Hemoglobin Single Subunit Proteins: Sequence --> Structure --> Function Anfinsen Experiment: Denature ribonuclease (RNase) Remove denaturant Assay for RNase activity -- does the protein regain its 3-D structure and its enzymatic activity? Molecular chaperones - Anfinsen cages for folding proteins Xu et al., 1997, Nature 388: 741 GroEL-GroES-(ADP)7 complex Clicker question: A good design for a stable folded protein is… 1) A polar/charged core with mostly nonpolar residues on the surface. 2) A nonpolar core with mostly polar/charged residues on the surface. 3) An even mix of polar/charged and nonpolar residues in the core and on the surface. 4) Fatty acids on the inside, ribonucleotides on the outside. 5) Ralph Lauren. Clicker question: A good design for a stable folded protein is… A) A polar/charged core with mostly nonpolar residues on the surface. B) A nonpolar core with mostly polar/charged residues on the surface. C) An even mix of polar/charged and nonpolar residues in the core and on the surface. D) Fatty acids on the inside, ribonucleotides on the outside. E) Ralph Lauren. The Protein Folding Problem: the sequence of a protein cannot (yet) be used to predict its 3D structure ? Protein Structure Prediction “Critical Assessment of techniques for Structure Prediction” (CASP 9) -- a competition For more information or to enter, see http://predictioncenter.org/ Winners earn an automatic “A+” in Bi 1 (retroactively, if necessary) Inverse Protein Folding Problem • Given a structure (or a functionality), identify an amino acid sequence whose fold will be that structure (exhibit that functionality). • Can we make designer proteins with desired functions? Foldit • New Nature Video - Foldit: Biology for gamers August 04, 2010 http://blogs.nature.com/news/thegreatbeyond/20 10/08/new_nature_video_foldit_biolog.html • From David Baker’s webpage: (http://depts.washington.edu/bakerpg/drupal/) Foldit is a revolutionary new computer game enabling you to contribute to important scientific research. Join this free online game and help us predict the folds of unsolved proteins as well as designing new proteins to cure diseases. We’re collecting data to find out if humans' pattern-recognition and puzzle-solving abilities make them more efficient than existing computer programs at pattern-folding tasks. If this turns out to be true, we can then teach human strategies to computers and fold proteins better than ever!