Author:

Keywords:

alpha/beta-barrels, protein structure, loops, molecular modeling, 3-dimensional structure, proteins, principles, evolution, sequence, synthase, design, sheet, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Biophysics, ALPHA/BETA-BARRELS, PROTEIN STRUCTURE, LOOPS, MOLECULAR MODELING, 3-DIMENSIONAL STRUCTURE, PROTEINS, PRINCIPLES, EVOLUTION, SEQUENCE, SYNTHASE, DESIGN, SHEET, Alcohol Oxidoreductases, Aldose-Ketose Isomerases, Amino Acid Sequence, Amylases, Carbohydrate Epimerases, Enzymes, Hydrogen Bonding, Indole-3-Glycerol-Phosphate Synthase, Models, Molecular, Molecular Sequence Data, Protein Conformation, Triose-Phosphate Isomerase, Tryptophan Synthase, 01 Mathematical Sciences, 06 Biological Sciences, 08 Information and Computing Sciences, Bioinformatics, 31 Biological sciences, 49 Mathematical sciences

Abstract:

A systematic survey of seven parallel alpha/beta-barrel protein domains, based on exhaustive structural comparisons, reveals that a sizable proportion of the alpha-beta-loops in these proteins-20 out of a total of 49-belong to either one of two loop types previously described by Thornton and co-workers. Six loops are of the alpha-beta-1 type, with one residue between the alpha-helix and beta-strand, and 13 are of the alpha-beta-3 type, with three residues between the helix and the strand. Protein fragments embedding the identified loops, and termed alpha-beta-connections since they contain parts of the flanking helix and strand, have been analyzed in detail revealing that each type of connection has a distinct set of conserved structural features. The orientation of the beta-strand relative to the helix and loop portions is different owing to a very localized difference in backbone conformation. In alpha-beta-1 connections, the chain enters the beta-strand via a residue adopting an extended conformation, while in alpha-beta-3 it does so via a residue in a near alpha-helical conformation. Other conserved structural features include distinct patterns of side chain orientation relative to the beta-sheet surface and of main chain H-bonds in the loop and the beta-strand moieties. Significant differences also occur in packing interactions of conserved hydrophobic residues situated in the last turn of the helix. Yet the alpha-helix surface of both types of connections adopts similar orientations relative to the barrel sheet surface. Our results suggest furthermore that conserved hydrophobic residues along the sequence of the connections, may be correlated more with specific patterns of interactions made with neighboring helices and sheet strands than with helix/strand packing within the connection itself. A number of intriguing observations are also made on the distribution of the identified alpha-beta-1 and alpha-beta-3 loops within the alpha/beta-barrel motifs. They often occur adjacent to each other; alpha-beta-3 loops invariably involve even numbered beta-strands, while alpha-beta-1 loops involve preferentially odd beta-strands; all the analyzed proteins contain at least one alpha-beta-3 loop in the first half of the eightfold alpha/beta-barrel. Possible origins of all these observations, and their relevance to the stability and folding of parallel alpha/beta-barrel motifs are discussed.