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Bioinformatics Master Course Protein Data Bank Protein Primary Structure C C E E N Bioinformatics master course N T T R R DNA/Protein structure-function E E F B F B analysis and prediction O I O I R O DNA/Protein structure-function R O I I I I N N N N T F analysis and prediction T F E O E O SCHEDULE G R G R R M R M A A A A T T T T http://www.few.vu.nl/onderwijs/roosters/rooster-vak-januari07.html I I Lecture 1: Protein Structure Basics (1) I I V C V C http://www.few.vu.nl/onderwijs/roosters/rooster-vak-voorjaar07.html E S E S V V U U Centre for Integrative Bioinformatics VU (IBIVU) Centre for Integrative Bioinformatics VU (IBIVU) Faculty of Exact Sciences / Faculty of Earth and Life Sciences Faculty of Exact Sciences / Faculty of Earth and Life Sciences The first protein structure in 1960: Protein Data Bank Myoglobin (Sir John Kendrew) Primary repository of protein teriary structures http://www.rcsb.org/pdb/home/home.do Dickerson’s formula: equivalent Protein primary structure to Moore’s law 20 amino acid types A generic residue Peptide bond n = e 0.19( y-1960) where y is the year. SARS Protein From Staphylococcus Aureus 1 MKYNNHDKIR DFIIIEAYMF RFKKKVKPEV 31 DMTIKEFILL TYLFHQQENT LPFKKIVSDL 61 CYKQSDLVQH IKVLVKHSYI SKVRSKIDER 91 NTYISISEEQ REKIAERVTL FDQIIKQFNL 121 ADQSESQMIP KDSKEFLNLM MYTMYFKNII On 27 March 2001 there were 12,123 3D protein 151 KKHLTLSFVE FTILAIITSQ NKNIVLLKDL 181 IETIHHKYPQ TVRALNNLKK QGYLIKERST structures in the PDB: Dickerson’s formula predicts 211 EDERKILIHM DDAQQDHAEQ LLAQVNQLLA 241 DKDHLHLVFE 12,066 (within 0.5%)! 1 Protein secondary structure Protein structure hierarchical levels PRIMARY STRUCTURE (amino acid sequence) SECONDARY STRUCTURE (helices, strands) Alpha-helix Beta strands/sheet VHLTPEEKSAVTALWGKVNVD EVGGEALGRLLVVYPWTQRFF ESFGDLSTPDAVMGNPKVKAH GKKVLGAFSDGLAHLDNLKGTF ATLSELHCDKLHVDPENFRLLG NVLVCVLAHHFGKEFTPPVQAA YQKVVAGVANALAHKYH SARS Protein From Staphylococcus Aureus 1 MKYNNHDKIR DFIIIEAYMF RFKKKVKPEV DMTIKEFILL TYLFHQQENT SHHH HHHHHHHHHH HHHHHHTTT SS HHHHHHH HHHHS S SE 51 LPFKKIVSDL CYKQSDLVQH IKVLVKHSYI SKVRSKIDER NTYISISEEQ EEHHHHHHHS SS GGGTHHH HHHHHHTTS EEEE SSSTT EEEE HHH 101 REKIAERVTL FDQIIKQFNL ADQSESQMIP KDSKEFLNLM MYTMYFKNII HHHHHHHHHH HHHHHHHHHH HTT SS S SHHHHHHHH HHHHHHHHHH 151 KKHLTLSFVE FTILAIITSQ NKNIVLLKDL IETIHHKYPQ TVRALNNLKK HHH SS HHH HHHHHHHHTT TT EEHHHH HHHSSS HHH HHHHHHHHHH 201 QGYLIKERST EDERKILIHM DDAQQDHAEQ LLAQVNQLLA DKDHLHLVFE HTSSEEEE S SSTT EEEE HHHHHHHHH HHHHHHHHTS SS TT SS TERTIARY STRUCTURE (fold) QUATERNARY STRUCTURE (oligomers) Protein folding problem PRIMARY STRUCTURE (amino acid sequence) Each protein sequence “knows” how to fold into its VHLTPEEKSAVTALWGKVNVD EVGGEALGRLLVVYPWTQRFF tertiary structure. We still do ESFGDLSTPDAVMGNPKVKAH not understand how and why GKKVLGAFSDGLAHLDNLKGTF ATLSELHCDKLHVDPENFRLLG NVLVCVLAHHFGKEFTPPVQAA SECONDARY STRUCTURE (helices, strands) YQKVVAGVANALAHKYH 1-step process 2-step process The 1-step process is based on a hydrophobic collapse; the 2-step process, more common in forming larger proteins, is called the TERTIARY STRUCTURE (fold) framework model of folding Globin fold β sandwich α protein β protein myoglobin immunoglobulin PDB: 1MBN PDB: 7FAB 2 A fold in α +β protein TIM barrel ribonuclease A PDB: 7RSA α / β protein Triose phosphate IsoMerase PDB: 1TIM The red balls represent waters that are ‘bound’ to the protein based on polar contacts α helix β sheet An α helix has the following features: • every 3.6 residues make one turn, • the distance between two turns is 0.54 nm, • the C=O (or N-H) of one turn is hydrogen bonded to N-H (or C=O) The β sheet structure found of the neighboring turn -- in RNase A the H-bonded N atom is 4 residues up in the chain A β sheet consists of two or more hydrogen bonded β strands. The two neighboring β strands may be parallel if they are aligned in the same (a) ideal right-handed α helix. C: green; O: red; N: blue; H: not shown; direction from one terminus (N or C) to the other, or anti-parallel if they hydrogen bond: dashed line. (b) The right-handed helix without α are aligned in the opposite direction. showing atoms. (c) the left-handed α helix (rarely observed). Homology-derived Secondary2 Structure of Proteins . (HSSP) 5 Sander & Schneider, 1991 25% But remember there are homologous relationships at very low identity levels (<10%)! 3 RMSD: Two superposed protein structures 2.5 (with two well-superposed helices) ) Chotia & Lesk, 1986 Ǻ 2.0 Root mean square deviation (RMSD) is typically calculated 1.5 between equivalent C α atoms 1.0 Red : well 0.5 superposed RMSD of backbone atoms ( atoms RMSDbackbone of Blue : low match 0.0 quality 100 75 50 25 0 C5 anaphylatoxin -- human (PDB code 1kjs) and pig (1c5a)) % identical residues in protein core proteins are superposed Secondary structure hydrophobity patterns Burried and Edge strands ALPHA-HELIX: Hydrophobic-hydrophilic 2-2 residue periodicity patterns BETA-STRAND: Edge strands, hydrophobic- hydrophilic 1-1 residue periodicity patterns; Edge Parallel β-sheet burried strands often have consecutive hydrophobic residues Buried OTHER: Loop regions contain a high proportion of small polar residues like alanine, glycine, serine and threonine. The abundance of glycine is due to its flexibility and proline for entropic reasons relating to the observed rigidity in its kinking the main-chain. Anti-parallel β-sheet As proline residues kink the main-chain in an incompatible way for helices and strands, they are normally not observed in these two structures (breakers), although they can occur in the N- terminal two positions of α-helices. Flavodoxin fold Flavodoxin family - TOPS diagrams (Flores et al., 1994) 4 3 2 To date, all α/β structures deposited in 5 4 3 1 2 5( βα ) fold the PDB start with a β- 5 1 strand! 4 Protein structure evolution Protein structure evolution Insertion/deletion of secondary structural Insertion/deletion of structural domains can elements can ‘easily’ be done at loop sites ‘easily’ be done at loop sites N C A domain is a: Identification of domains is essential for: • High resolution structures (e.g. Pfuhl & • Compact, semi-independent unit Pastore, 1995). (Richardson, 1981). • Sequence analysis (Russell & Ponting, 1998) • Stable unit of a protein structure that • Multiple alignment methods can fold autonomously (Wetlaufer, • Sequence database searches 1973). • Prediction algorithms • Recurring functional and evolutionary • Fold recognition module (Bork, 1992). • Structural/functional genomics “Nature is a tinkerer and not an inventor” (Jacob, 1977). Domain connectivity Domain size •The size of individual structural domains varies widely from 36 residues in E-selectin to 692 residues in lipoxygenase-1 (Jones et al., 1998), the majority (90%) having less than 200 residues (Siddiqui and Barton, 1995) with an average of about 100 residues (Islam et al., 1995). •Small domains (less than 40 residues) are often stabilised by metal ions or disulphide bonds. • Large domains (greater than 300 residues) are likely to consist of multiple hydrophobic cores (Garel, 1992). 5 Domain characteristics Domain fusion •Domains are genetically mobile units, and Genetic mechanisms influencing the layout of multidomain families are found in all three kingdoms multidomain proteins include gross (Archaea, Bacteria and Eukarya) rearrangements such as inversions, translocations, deletions and duplications, homologous •The majority of proteins, 75% in unicellular recombination, and slippage of DNA polymerase organisms and >80% in metazoa, are multidomain during replication (Bork et al., 1992). proteins created as a result of gene duplication events (Apic et al., 2001). Although genetically conceivable, the transition from two single domain proteins to a multidomain •Domains in multidomain structures are likely to have protein requires that both domains fold correctly once existed as independent proteins, and many and that they accomplish to bury a fraction of the domains in eukaryotic multidomain proteins can be previously solvent-exposed surface area in a newly found as independent proteins in prokaryotes generated inter-domain surface. (Davidson et al., 1993). Domain fusion example Inferring functional relationships Vertebrates have a multi-enzyme protein (GARs- Domain fusion – Rosetta Stone method AIRs-GARt) comprising the enzymes GAR synthetase (GARs), AIR synthetase (AIRs), and GAR transformylase (GARt) 1. If you find a genome with a fused multidomain protein, In insects, the polypeptide appears as GARs- and another genome (AIRs)2-GARt. However, GARs-AIRs is encoded featuring these separately from GARt in yeast, and in bacteria each domains as separate domain is encoded separately (Henikoff et al., proteins, then these 1997). separate domains can be predicted to be functionally linked 1GAR: glycinamide ribonucleotide synthetase (“guilt by association”) AIR: aminoimidazole ribonucleotide synthetase David Eisenberg, Edward M. Marcotte, Ioannis Xenarios & Todd O. Yeates Inferring functional relationships Fraction exposed residues against chain length Phylogenetic profiling If in some genomes, two (or more) proteins co-occur, and in some other genomes they cannot be found, then this joint presence/absence can be taken as evidence for a functional link between these proteins David Eisenberg, Edward M. Marcotte, Ioannis Xenarios & Todd O. Yeates 6 Fraction exposed residues against chain length Fraction exposed residues against chain length Fraction exposed residues against chain length Fraction exposed residues against chain length Fraction exposed residues against chain length Fraction exposed residues against chain length
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