1CMSC 838T – Lecture 6CMSC 838T – Lecture 6X Protein structure prediction0 Predict protein 3D structure from (amino acid) sequence0 One step closer to useful biological knowledge0 Sequence → secondary structure → 3D structure → function5' atgcccaagctgaat … 3'atg ccc aag ctg aat …M P K L N …CMSC 838T – Lecture 6Protein Structure PredictionX Protein structure0 Assume in most cases, 3D structure → biological functionO Lock & key model of enzyme function (docking)0 Folding problem: protein sequence ⇔ 3D structure0 Structure prediction → protein design, drug design, etc …0 The “holy grail” of bioinformaticsX Prediction is possible because0 Sequence information uniquely determines 3D structure0 Sequence similarity (>50%) tends to imply structural similarityX Prediction is necessary because0 DNA sequence data » protein sequence data » structure data2CMSC 838T – Lecture 6Protein Structure Prediction & AlignmentX Protein structure0 Interatomic forces0 Secondary structure0 Tertiary structureX Structure prediction0 Secondary structure0 3D structureO Ab initioO Comparative modelingO ThreadingX Structure alignment0 3D structure alignment0 Protein dockingCMSC 838T – Lecture 6Amino Acid (AA.) – Structure & ResiduesX Basic structureX 20 residues0 Residues can share similar biochemical properties3CMSC 838T – Lecture 6Peptides & ProteinsX Protein synthesis0 Ribosome translates mRNAinto sequence of amino acids0 Amino acids connected by peptide bondX Amino acid sequences0 < 40 → peptide0 > 40 → proteinRibosomesPeptides / ProteinsCMSC 838T – Lecture 6Inter-atomic ForcesX Covalent bond (short range, very strong)0 Binds atoms into molecules / macromoleculesX Hydrogen bond (short range, strong)0 Binds two polar groups (hydrogen + electronegative atom)X Disulfide bond / bridge (short range, very strong)0 Covalent bond between sulfhydryl (sulfur + hydrogen) groups0 Sulfhydryl found in cysteine residues0 Two sulfhydryl groups oxidize → disulfide (S–S) bond0 Oxidation may require external oxidant (enzyme)0 Hydrogen & disulfide bonds help stablize 3D protein structure4CMSC 838T – Lecture 6Inter-atomic ForcesX Hydrophobic / hydrophillic interaction (weak)0 Hydrogen bonding w/ H2O in solutionO Non-polar residues interfere (hydrophobic)O Polar residues participate (hydrophillic)0 Main cause of globular 3D protein → protect hydrophobic coreX Charge-charge, charge-dipole, dipole-dipole (weak)0 Electrostatic attractive forceX Van der Waal’s interaction (very weak)0 Nonspecific electrostatic attractive force0 From transitive attractions between instantaneous dipolesX Steric interaction (very short range, very strong)0 Repulsive force between atomic nucleiCMSC 838T – Lecture 6Types of Inter-atomic ForcesCovalent Bondvan der Waal InteractionHydrogen BondCharge-charge Interaction+–++++–––––+++–––––––+++++++–Negative ChargePositive ChargeNo ChargeAtoms & MoleculesH2OC=O NHSH, SH → S S+–+–––Disulfide Bond / Bridge5CMSC 838T – Lecture 6Inter-atomic Forces – Hydrophobicity PlotX Hydrophobicity0 Meaningful in context of protein sequence region0 Hydrophobicity plot → track local hydrophobic residues0 Many local hydrophobic residues → hydrophobic regionHuman tumor antigen p53 (window = 19 residues)CMSC 838T – Lecture 6Inter-atomic Forces – Lennard-Jones PotentialX Forces0 Van der Waal’s (attractive, far)0 Steric interaction (repulsive, close)X Lennard-Jones0 Plot of pair potential energy vs. distance0 Local minima (energy well) is stable distance for two atomsDistance →Potential energy →6CMSC 838T – Lecture 6Proteins – Backbone FlexibilityX Peptide torsion angles0 Limited degree of freedom for peptide backbone0 Can plot angle of bonds around Cα0 Limits secondary structureRamachandran PlotGlycine (G)Glycine: smaller → more flexibilityCαCMSC 838T – Lecture 6Protein Structure Prediction & AlignmentX Protein structure0 Interatomic forces0 Secondary structure0 Tertiary structureX Structure prediction0 Secondary structure0 3D structureO Ab initioO Comparative modelingO ThreadingX Structure alignment0 3D structure alignment0 Protein docking7CMSC 838T – Lecture 6Proteins – Secondary StructureX α-helix (30-35%)0 Hydrogen bond between C=O (carbonyl) & NH (amine) groups within strand (4 positions apart)0 3.6 residues / turn, 1.5 Å rise / residue0 Typically right hand turn0 Most abundant secondary structure0 α-helix formers: A,C,L,M,E,Q,H,KX β-sheet / β-strand (20-25%)0 Hydrogen bond between groups across strands0 Forms parallel and antiparallel pleated sheets0 Amino acids less compact – 3.5 Å between adjacent residues0 Residues alternate above and below β-sheet0 β-sheet formers: V,I,P,T,WCMSC 838T – Lecture 6Proteins – Parallel & Antiparallel β-sheet8CMSC 838T – Lecture 6Proteins – Secondary StructureX Coil (40-50%)0 Generally speaking, anything besides α-helix, β-sheet, β-turnX β-turn0 Short turn (4 residues)0 Hydrogen bond between C=O & NH groups within strand (3 positions apart)0 Usually polar, found near surface0 β-turn formers: S,D,N,P,RX Loop0 Regions between α-helices and β-sheets0 On the surface, vary in length and 3D configurations0 Do not have regular periodic structures0 Loop formers: small polar residuesCMSC 838T – Lecture 6Proteins – Secondary StructureX Properties0 Secondary structure is very context-dependentO Relies on substructures in nearby environmentO β-sheet stabilized by hydrogen bonds w/ other β-sheet O α-helix more stable on its own0 Prediction is difficultX Uses0 Can help predict 3D protein structureO Intermediate step in predictionO Use topology of secondary structures to predict 3D0 Can help model protein folding processO Sequences first form secondary structures as frameO 3D structure formed by attaching substructures to frame9CMSC 838T – Lecture 6Proteins – Structural ClassesX Can label proteins by dominant structureX SCOP (Structural Classification Of Proteins)0 Class αα-helices connected by loops0 Class β antiparallel sheets0 Class α / β parallel β-sheets with intervening α-helices0 Class α + β segregated α-helices and antiparallel β-sheets0 Multidomain combinations of classes0 Membrane membranes & cell surface proteins0 Small proteins metal ligand, heme, and/or disulfide bridges0 Coiled coil 2-3 α-helices coiled around each other0 Low resolution0 Peptides not true classes0 DesignedCMSC 838T – Lecture