Proteins Proteins control the biological functions of cellular organisms e.g. metabolism, blood...
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Transcript of Proteins Proteins control the biological functions of cellular organisms e.g. metabolism, blood...
Proteins
Proteins control the biological functions of cellular organisms e.g. metabolism, blood clotting, immune system
Building blocks – amino acidsamino acids
amino group (NH2), carboxyl group (COOH), side chain R
Protein sequence and structure
Protein alphabet consists of 20 amino acids
Sequence view Structure view
ADKELKFLVVDDFSTMRRIV.....
Protein structure and function
Function is determined by 3D shape/structure
ThrombinFacilitates blood clotting
HirudinAnticoagulant
(blocks active site)
Protein structure and function
Structure conserves better evolution information
1MBC: VLSEGEWQLVLHVWAKVE.....
2FAL: XSLSAAEADLAGKSWAPV.....
Myoglobin family
Structural Bioinformatics
Pairwise alignment algorithms DALI (Holm and Sander, Journal of Molecular Biology, 1993) LOCK (Singh and Brutlag, ISMB, 1997) CE (Shindyalov and Bourne, Protein Engineering, 1998) SSM (Krissinel and Henrick, Acta Cryst., 2004) Ye et al. JBCB, 2004
Multiple alignment algorithms Gerstein and Levitt, ISMB, 1996: Iterative dynamic programming SSAP (Orengo and Taylor, Methods Enymol., 1996): Two-level DP Leibowitz et al., ISMB, 1999): Geometric hashing CE-MC (Guda et al., PSB, 2001) MAMMOTH (Lupyan et al., Bioinformatics, 2005) MAPSCI (Ye at al., WABI, 2006)
Structural Bioinformatics
Homology detection Hidden Markov models (Jaakola et al., JCB, 2000) Spectrum, Mismatch kernel (Leslie et al., Bioinformatics, 2002) Structure kernel (Qiu et al., Bioinformatics, 2007)
Protein structure prediction Jones and Hadley, Bioinformatics: Sequence, structure and databanks. 2000. FUGUE (Shi et al., J. Mol. Biol., 2001) SCOP (Andreeva, Nucleic Acids Res., 2004)
Protein docking Shoichet et al., J. Comput. Chem., 1992. Choi et al., WABI, 2004. Wang et al., PSB, 2005. Sousa et al., Proteins, 2006.
Pairwise Structure Alignment Given two proteins represented by the Cα atoms (backbone)
f ind 3D transformation that superimposes a large number of the C α atoms
ensure that overall distance between matched pairs is as small as possible
Trade-off between number of matches and total distance between
Pairwise Structure Alignment Ye et al. JBCB 2004
Uses orientation independent representation of proteins based on the fact that Cα atoms are ~4 Ǻ apart
Pairwise Structure Alignment Ye et al. JBCB 2004
The protein is represented as a sequence of angle triplets{(α1, β1, γ1), (α2, β2, γ2), …, (αn, βn, γn) }
Pairwise Structure Alignment Ye et al. JBCB 2004
Compute a local alignment based on angle representation
Find maximal subset of runs with similar transformation matrices
Pairwise Structure Alignment Ye et al. JBCB 2004
The main algorithm Compute the angle based representation Align the angle based representation Identify runs with similar transformation matrices Compute initial structural alignment Refine the alignment iteratively
Running time is ~(m+n)2 where m, n are the protein lengths
Multiple Structure Alignment Given a set of proteins represented by the Cα atoms (backbone)
find a simultaneous alignment of all structures
find a consensus structure that represents all of them
Multiple Structure Alignment The main algorithm
find initial consensus structure (one of the given proteins) pairwise align the consensus and each of the proteins merge the pairwise alignments from previous step recompute the consensus protein; repeat from step 2
Merging the pairwise alignments similar to sequence case
P1 = BBCA, P2 = CBBA, P3 = BCCA
P1: -BBCA, P1:= BBCA P: -BBCA
P2: CBB-A, P3:= BCCA P: CBB-A
P: -BCCA