BMI 731Biology … Protein…A single amino acid substitution in a protein causes sickle-cell disease…What the.....!?Why do we care about structure?Structural InformationPDB Content GrowthProtein?Structure…Structure cont…Basic measurements on structures…Bond LengthBond Angle…Dihedral AnglesSlide 15Ramachandran / phi-psi plotLevels of Structure…Primary structure…Secondary structureThe -helixThe -sheetRamachandran/phi-psi plotTertiary structure…Quaternary structure…Classification…Databases of structural classificationSlide 27Why Structure Alignment?How do we recognize structural similarities?Algorithms for Structure AlignmentDALIVAST-Vector Alignment Search ToolLOCKWhere is the data?MMDB by NCBI…Slide 37Slide 38Images..Images…Images… (NMR… EPR…)X-ray crystallography.ThanksBMI 731BMI 731Protein Structures and Protein Structures and Related Database SearchesRelated Database SearchesBiology … Protein…Biology … Protein… DNA(Genotype)ProteinA single amino acid substitution in a protein causes sickle-A single amino acid substitution in a protein causes sickle-cell disease…cell disease…What the.....!?What the.....!?Why do we care about Why do we care about structure?structure?•In the factory of living cells, proteins are the In the factory of living cells, proteins are the workers, performing a variety of biological workers, performing a variety of biological tasks.tasks.•Each protein has a particular 3-D structure Each protein has a particular 3-D structure that determines its function.that determines its function.•Protein structure is more conserved than Protein structure is more conserved than protein sequence, and more closely related protein sequence, and more closely related to function.to function.•Sequence -> Structure -> FunctionSequence -> Structure -> FunctionStructural InformationStructural Information•Protein Data Bank: maintained by the Research Protein Data Bank: maintained by the Research Collaboratory of Structural Bioinformatics Collaboratory of Structural Bioinformatics (RCSB)(RCSB)–http://http://www.rcsb.org/pdbwww.rcsb.org/pdb//–> 15,000 structures of proteins> 15,000 structures of proteins–Also contains of structures of Protein/Nucleic Also contains of structures of Protein/Nucleic Acid Complexes, Nucleic Acids, CarbohydratesAcid Complexes, Nucleic Acids, Carbohydrates•Most structures are determined by X-ray Most structures are determined by X-ray crystallography. Other methods are NMR and crystallography. Other methods are NMR and electron microscopy (EM). Some structures are electron microscopy (EM). Some structures are also theoretically predicted.also theoretically predicted.PDB Content GrowthPDB Content GrowthProtein?Protein?•Protein are linear heteropolymers: Protein are linear heteropolymers: one or more polypeptide chainsone or more polypeptide chains•Building blocks: 20(?) amino acid Building blocks: 20(?) amino acid residues.residues.•Range from a few 10s-1000sRange from a few 10s-1000s•Three-dimensional shapes (“fold”) Three-dimensional shapes (“fold”) adopted vary enormously.adopted vary enormously.Structure…Structure…Structure cont…Structure cont…Basic measurements on Basic measurements on structures…structures…•Bond lengthsBond lengths•Bond anglesBond angles•Dihedral (torsion) anglesDihedral (torsion) anglesBond LengthBond Length•The distance between bonded atoms The distance between bonded atoms is constantis constant•Depends on the “type” of the bondDepends on the “type” of the bond•Varies from 1.0 Varies from 1.0 Å(C-H) to 1.5 Å(C-C)Å(C-H) to 1.5 Å(C-C)•BOND LENGTH IS A FUNCTION OF BOND LENGTH IS A FUNCTION OF THE POSITION OF TWO ATOMS.THE POSITION OF TWO ATOMS.Bond Angle…Bond Angle…•All bond angles are determined by All bond angles are determined by chemical makeup of the atoms involved, chemical makeup of the atoms involved, and are constant.and are constant.•Depends on the type of atom, and Depends on the type of atom, and number of electrons available for number of electrons available for bonding.bonding.•Ranges from 100Ranges from 100° to 180°° to 180° •BOND ANGLES IS A FUNCTION OF THE BOND ANGLES IS A FUNCTION OF THE POSITION OF THREE ATOMS.POSITION OF THREE ATOMS.Dihedral AnglesDihedral Angles•These are usually variableThese are usually variable•Range from 0-360Range from 0-360° in molecules° in molecules•Most famous are Most famous are , , , ,  and and •DIHEDRAL ANGLES ARE A FUNCTION DIHEDRAL ANGLES ARE A FUNCTION OF THE POSITION OF FOUR ATOMS.OF THE POSITION OF FOUR ATOMS.http://www.colby.edu/chemistry/OChem/DEMOS/dihedral.htmlhttp://www.colby.edu/chemistry/OChem/DEMOS/dihedral.htmlDihedral AnglesDihedral AnglesA torsion angles is defined by 4 atoms, A, B, C and D.When atoms A, B, C and D are mainchain atoms (ie. the carboxylic carbon, C1; the alpha carbon, C2 or C-alpha; and the amide group nitrogen, N), There are THREE repeating torsion angles along the backbone chain called phi, psi and omega.http://bmbiris.bmb.uga.edu/wampler/tutorial/prot2.htmlhttp://bmbiris.bmb.uga.edu/wampler/tutorial/prot2.htmlRamachandran / phi-psi plotRamachandran / phi-psi plothttp://www.biochem.ucl.ac.uk/~roman/procheck/manual/examples/plot_01.htmlLevels of Structure…Levels of Structure…1 - Primary structure1 - Primary structure2 - Secondary structure2 - Secondary structure3 - Tertiary structure3 - Tertiary structure4 - Quaternary structure4 - Quaternary structurePrimary structure…Primary structure…•This is simply the amino acid sequences This is simply the amino acid sequences of polypeptide chainsof polypeptide chainsSecondary structureSecondary structure•Local organization of protein backbone: Local organization of protein backbone: -helix, -helix, -strand (which assemble into -strand (which assemble into --sheet), turn and interconnecting loop.sheet), turn and interconnecting loop.The The -helix-helix•One of the most One of the most closely packed closely packed arrangement of arrangement of residues.residues.•Turn: 3.6 residuesTurn: 3.6 residues•Pitch: 5.4 Å/turnPitch: 5.4 Å/turnThe The -sheet-sheet•Backbone almost fully extended, loosely Backbone almost fully extended, loosely packed arrangement of residues.packed arrangement of residues.Ramachandran/phi-psi plotRamachandran/phi-psi plotTertiary structure…Tertiary