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Transcript
Protein structure Recommended reading • On protein structure and function – Branden & Tooze, Intro to Protein Structure – Lesk, Protein Architecture • On protein structure prediction – Salzberg & Searls, Kasif, Computational Methods in Molecular Biology – Setubal & Meidanis, Intro to Computational Molecular Biology Why? • Proteins are highly adapted to perform specific functions. Why? • Proteins are highly adapted to perform specific functions. • Functional properties depend on threedimensional structure. Why? • Proteins are highly adapted to perform specific functions. • Functional properties depend on threedimensional structure. • Three-dimensional structure form, on the basis of chemical laws, from linear chains of peptides (amino acids). What? • Most life functions are performed by proteins: – – – – – – scaffolding (cell walls) activity (muscle fiber) catalysts (enablers) enzymes (tools) transport (hemoglobin) binding (keys & switches) Whether? • ‘To understand the biological function of proteins we would .. Like to be able to deduce or predict the three-dimensional structure from the amino acid sequence.’ Whether? • ‘To understand the biological function of proteins we would .. Like to be able to deduce or predict the threedimensional structure from the amino acid sequence.’ • ‘This we cannot do.’ Whether? • ‘To understand the biological function of proteins we would .. Like to be able to deduce or predict the threedimensional structure from the amino acid sequence.’ • ‘This we cannot do.’ • ‘In spite of considerable efforts over the past 25 years, this folding problem is still unsolved and remains one of the most basic intellectual challenges in molecular biology.’ Proteins are polypeptide chains • There are 20 amino acids • Each amino acid has a central carbon atom, Ca • Each Ca has an attached amino group and a carboxyl group • Each Ca has an attached side chain • Adjacent peptides link through a peptide bond Amino acid groups • Hydrophobic amino acids – Alanine, Valine, Phenylalanine, Proline, Methionine, Isoleucine, Leucine • Charged amino acids – Aspartic acid, Glutamic acid, Lysine, Arginine • Polar amino acids – Serine, Threonine, Tyrosine, Histidine, Cyseine, Asparagine, Glutamine, Tryptophan • Glycine ‘Levels’ of protein structure Angles of the chain The conformational angles • • • • • Peptides are rigid groups There is rotational freedom at each Ca bond The N-Ca angle is called phi (f) The Ca-C’ angle is called psi (y) The peptide sequence and the phi-psi angles completely specify a three dimensional structure Constraints on conformation • Most phi-psi combinations can’t occur because they cause the side chain and main chain to collide • Permitted combinations are called Ramachandran plots Glycine’s structural role • Glycine (H side chain) has lots of freedom • Therefore, is good for creating unusual shapes • Therefore, glycine is highly conserved among homologous sequences (useful in prediction) Rotamers • ‘Long’ side chains interweave with the main chain • These staggered conformations are called rotamers • Some rotamers are energetically favorable and are preferred (useful in prediction) Metal atoms in proteins • Some amino acids bind metal atoms • These atoms are used in function and/or structure of the protein • Example: iron is used by hemoglobin for oxygen binding and transport • Example: ‘zinc fingers’ stabilize DNAbinding regions Motifs ‘Perhaps the most remarkable features of the [protein] molecule are its complexity and its lack of symmetry. The arrangement seems to be almost totally lacking in the kind of regularities which one instinctively anticipates, and it is more complicated than has been predicted by any theory of protein structure.’ – John Kendrick, 1958 Globular structure • Functional groups attached to rigid framework • Many compact regions • Hydrophobic core • Hydrophilic surface • Gaps may have water molecules Alpha helices • Predicted by Pauling, 1951 • Confirmed by Max Perutz on myoglobin structure • Consecutive residues with angles of ~-60 and -50 degrees • Question: how many residues per turn of helix? Beta sheets • Build from ‘distant’ subsequences • Form hydrogen bonds between C’=0 group and NH group • May be parallel or antiparallel Loop regions • Rich in charged and polar residues • Antiparallel connectors are hairpin turns Threading • Match protein to a relative (based on sequence similarity) • There aren’t too many (~1000) basic families of proteins Formal statement • Input: – – – – protein sequence core structural model score functions lower bound (temination condition) • Output: – a threading Methods • NP-hard! • Any combinatorial optimization method may be applied – Branch and bound – Genetic algorithm – Simulated annealing • Hundreds of submissions to CASP A beta sheet Abstract views of protein structure