Protein Structure: Classification, Databases, and Visualization for BCB 444/544X - Prof. D, Exams of Bioinformatics

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Protein Structure: Classification, Databases, Visualization 11/07/05 D Dobbs ISU - BCB 444/544X 1 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 1 11/7/05 Protein Structure: Classification, Databases, Visualization 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 2 Announcements BCB 544 Projects - Important Dates: Nov 2 Wed noon - Project proposals due to David/Drena Nov 4 Fri PM - Approvals/responses & tentative presentation schedule to students Dec 2 Fri noon - Written project reports due Dec 5,7,8,9 class/lab - Oral Presentations (20') (Dec 15 Thurs = Final Exam) 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 3 Bioinformatics Seminars Nov 7 Mon 12:10 IG Faculty Seminar in 101 Ind Ed II Inborn Errors of Metabolism in Humans & Animal Models Matt Ellinwood, Animal Science, ISU Nov 10 Thurs 3:40 Com S Seminar in 223 Atanasoff Computational Epidemiology Armin R. Mikler, Univ. North Texas http://www.cs.iastate.edu/~colloq/#t3 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 4 Bioinformatics Seminars CORRECTION: Next week - Baker Center/BCB Seminars: (seminar abstracts available at above link) Nov 14 Mon 1:10 PM Doug Brutlag, Stanford Discovering transcription factor binding sites Nov 15 Tues 1:10 PM Ilya Vakser, Univ Kansas Modeling protein-protein interactions both seminars will be in Howe Hall Auditorium 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 5 Protein Structure & Function: Analysis & Prediction Mon Protein structure: classification, databases, visualization Wed Protein structure: prediction & modeling Thurs Lab Protein structure prediction Fri Protein-nucleic acid interactions Protein-ligand docking 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 6 Reading Assignment (for Mon-Fri) Mount Bioinformatics • Chp 10 Protein classification & structure prediction http://www.bioinformaticsonline.org/ch/ch10/index.html • pp. 409-491 • Ck Errata: http://www.bioinformaticsonline.org/help/errata2.html Other? Additional reading assignments for BCB 544 Protein Structure: Classification, Databases, Visualization 11/07/05 D Dobbs ISU - BCB 444/544X 2 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 7 Review last lecture: RNA Structure Prediction Algorithms 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 8 RNA structure prediction strategies 1) Energy minimization (thermodynamics) 2) Comparative sequence analysis (co-variation) 3) Combined experimental & computational Secondary structure prediction 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 9 1) Energy minimization method What are the assumptions? Native tertiary structure or "fold" of an RNA molecule is (one of) its lowest free energy configuration(s) Gibbs free energy = ΔG in kcal/mol at 37°C = equilibrium stability of structure lower values (negative) are more favorable Is this assumption valid? in vivo? - this may not hold, but we don't really know 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 10 Gibbs free energy: ΔG Gibbs Free energy (G) is formally defined in terms of state functions enthalpy & entropy, & state variable, temperature G = H - TS ΔG = ΔH - TΔS (for constant temp) Enthalpy (H) = amount of heat absorbed by a system at constant pressure Entropy (S) = measure of the amount of disorder or randomness in a system Note = this is not the same as "entropy" in information theory, but is related, see: http://en.wikipedia.org/wiki/Information_theory 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 11 Gibbs free energy: ΔG Gibbs free energy for formation of an RNA or protein structure = ΔG° = equilibrium stability of that structure at a specific temperature (kcal/mol at 37°C) ΔG° = -RT lnKeq R = gas constant 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 12 Nearest-neighbor parameters Most methods for free energy minimization use nearest-neighbor parameters (derived from experiment) for predicting stability of an RNA secondary structure (in terms of ΔG at 37°C) & most available software packages use the same set of parameters: Mathews, Sabina, Zuker & Turner, 1999 Protein Structure: Classification, Databases, Visualization 11/07/05 D Dobbs ISU - BCB 444/544X 5 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 25 Amino Acids Each of 20 different amino acids has different "R-Group," side chain attached to Cα 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 26 Peptide bond is rigid and planar 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 27 Hydrophobic Amino Acids 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 28 Charged Amino Acids 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 29 Polar Amino Acids 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 30 Certain side-chain configurations are energetically favored (rotamers) Ramachandran plot: "Allowable" psi & phi angles Protein Structure: Classification, Databases, Visualization 11/07/05 D Dobbs ISU - BCB 444/544X 6 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 31 Glycine is smallest amino acid R group = H atom • Glycine residues increase backbone flexibility because they have no R group 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 32 Proline is cyclic • Proline residues reduce flexibility of polypeptide chain • Proline cis-trans isomerization is often a rate-limiting step in protein folding • Recent work suggests it also may also regulate ligand binding in native proteins -Andreotti 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 33 Cysteines can form disulfide bonds • Disulfide bonds (covalent) stabilize 3-D structures • In eukaryotes, disulfide bonds are found only in secreted proteins or extracellular domains 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 34 Globular proteins have a compact hydrophobic core Packing of hydrophobic side chains into interior is main driving force for folding Problem? Polypeptide backbone is highly polar (hydrophilic) due to polar -NH and C=O in each peptide unit; these polar groups must be neutralized Solution? Form regular secondary structures, e.g., α-helix, β-sheet, stabilized by H-bonds 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 35 Exterior surface of globular proteins is generally hydrophilic Hydrophobic core formed by packed secondary structural elements provides compact, stable core "Functional groups" of protein are attached to this framework; exterior has more flexible regions (loops) and polar/charged residues Hydrophobic "patches" on protein surface are often involved in protein-protein interactions 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 36 Protein Secondary Structures α−Helix β− Sheets Loops Coils Protein Structure: Classification, Databases, Visualization 11/07/05 D Dobbs ISU - BCB 444/544X 7 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 37 α - Helix Most abundant 2' structure in proteins Average length = 10 aa's (~10 Angstroms) • Length varies from 5-40 aa's • Alignment of H-bonds creates dipole moment (positive charge at NH end) • Often at surface of core, with hydrophobic residues on inner-facing side, hydrophilic on other side 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 38 α−helix is stabilized by H-bonds between ~ every 4th residue C = black O = red N = blue 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 39 R-groups are on outside of α−helix 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 40 Types of α−helices "Standard" α−helix: 3.6 residues per turn H-bonds between C=0 of residue n and NH of residue n + 4 Helix ends are polar; almost always on surface of protein Other types of helices? n + 5 = π helix n + 3 = 310 helix 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 41 Certain amino acids are "preferred" & others are rare in α−helices • Ala, Glu, Leu, Met = good helix formers • Pro, Gly Tyr, Ser = very poor • Amino acid composition & distribution varies, depending on on location of helix in 3-D structure 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 42 β-Strands & Sheets H-bonds formed between 5-10 consecutive residues in one portion of chain with another set of 5-10 residues farther down chain Interacting regions may be adjacent (with short loop between) or far apart β-sheets usually have all strands either parallel or antiparallel Protein Structure: Classification, Databases, Visualization 11/07/05 D Dobbs ISU - BCB 444/544X 10 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 55 Simple motifs combine to form domains 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 56 Large polypeptide chains fold into several domains 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 57 6 main classes of protein structure 1) α Domains • Bundles of helices connected by loops 2) β Domains • Mainly antiparallel sheets, usually with 2 sheets forming sandwich 3) α/β Domains • Mainly parallel sheets with intervening helices, also mixed sheets 4) α+β Domains • Mainly segregated helices and sheets 5) Multidomain (α & β) • Containing domains from more than one class 6) Membrane & cell-surface proteins 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 58 α-domain structures: coiled-coils 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 59 α-domain structures: 4-helix bundles 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 60 All-α proteins: Globins Protein Structure: Classification, Databases, Visualization 11/07/05 D Dobbs ISU - BCB 444/544X 11 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 61 β-domain structures Anti-parallel β structures Functionally most diverse Includes: • Up-and-down sheets or barrels • Propeller-like structures • Jelly roll barrels (from Greek key motifs) 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 62 Up-and-down sheets and barrel 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 63 Up-and-down sheets can form propeller-like structures 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 64 Greek key motifs can form jelly roll barrels 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 65 α/β-domain structures 3 main classes TIM barrel = Core of twisted parallel strands close together Rossman fold = open twisted sheet surrounded by helices on both sides Leucine-rich motif = specific pattern of Leu residues, strands form a curved sheet with helices on outside 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 66 TIM barrel Rossman fold Protein Structure: Classification, Databases, Visualization 11/07/05 D Dobbs ISU - BCB 444/544X 12 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 67 Leucine rich motifs can form α/β horseshoes 11/07/05 D Dobbs ISU - BCB 444/544X: Protein Structure: Classification, Databases, Visualization 68 Protein structure databases, structural classification & visualization PDB = Protein Data Bank http://www.rcsb.org/pdb/ (RISC) - several different structure viewers MMDB = Molecular Modeling Database http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure (NCBI Entrez) - Cn3D viewer SCOP = Structural Classification of Proteins Levels reflect both evolutionary and structural relationships CATH = Classification by Class, Architecture, Topology and Homology