Multiple alignments

Attempts have also been made at predicting the secondary stmcture of proteins from the propensities for residues to occur in the a-helix or the P-sheet (23). However, the assignment of secondary stmcture for a residue only has an average accuracy of about 60%. A better success rate (70%) is achieved when multiple-aligned sequences having high sequence similarity are available. 

A prior distribution for sequence profiles can be derived from mixtures of Dirichlet distributions [16,51-54]. The idea is simple Each position in a multiple alignment represents one of a limited number of possible distributions that reflect the important physical forces that determine protein structure and function. In certain core positions, we expect to get a distribution restricted to Val, He, Met, and Leu. Other core positions may include these amino acids plus the large hydrophobic aromatic amino acids Phe and Trp. There will also be positions that are completely conserved, including catalytic residues (often Lys, GIu, Asp, Arg, Ser, and other polar amino acids) and Gly and Pro residues that are important in achieving certain backbone conformations in coil regions. Cys residues that form disulfide bonds or coordinate metal ions are also usually well conserved. 

A prior distribution of the probabilities of the 20 amino acids at a particular position in a multiple alignment can be represented by a Dirichlet distribution, described in Section lI.E. That is, it is an expression of the values of the probabilities of each residue type r, where r ranges from 1 to 20, and E( i0,. = 1 ... 

Thompson and Goldstein [89] improve on the calculations of Stolorz et al. by including the secondary structure of the entire window rather than just a central position and then sum over all secondary strucmre segment types with a particular secondary structure at the central position to achieve a prediction for this position. They also use information from multiple sequence alignments of proteins to improve secondary structure prediction. They use Bayes rule to fonnulate expressions for the probability of secondary structures, given a multiple alignment. Their work describes what is essentially a sophisticated prior distribution for 6 i(X), where X is a matrix of residue counts in a multiple alignment in a window about a central position. The PDB data are used to form this prior, which is used as the predictive distribution. No posterior is calculated with posterior = prior X likelihood. 

Prediction methods for secondary structure benefit from multiple alignment of homologous proteins... 

Several programs are now available that use multiple alignment of homologous proteins for prediction of secondary structure. One such program, called PHD, which was developed by Chris Sander and coworkers, EMBL, Heidelberg, has reached a mean accuracy of prediction of 72% for new structures. 

The aim of the fust dimension breadth is to reveal sequence-function relationships by comparing protein sequences by sequence similarity. Simple bioinformatic algorithms can be used to compare a pair of related proteins or for sequence similarity searches e.g., BLAST (Basic Local Alignment Search Tool). Improved algorithms allow multiple alignments of larger number of proteins and extraction of consensus sequence pattern and sequence profiles or structural templates, which can be related to some functions, see e.g., under http //www. expasy.ch/tools/ similarity. 

Fig. 2a-d. Multiple alignment of primary structures from 36 PHA synthases. A comparison of amino acid sequences derived from PH A synthase genes is shown. Amino acids are specified by the standard one-letter abbreviations. The consensus sequence represents amino acid residues (shaded) which are present in at least 50% of the PHA synthases. Highly conserved amino acids, which are present in at least 70% of the PHA synthases, are additionally underlined in the consensus sequence and the eight amino acid residues, which are present in all PHA synthases, are indicated as bold letters. See Table 1 for references... 

Ryan D, Parviz BA, Linder V, Semetey V, Sia SK, Su J, Mrksich M, Whitesides GM (2004) Patterning multiple aligned self-assembled monolayers using light. Langmuir 20 9080-9088... 

GCRDb entry is not much more extensive than what is found in the EMBL nucleotide sequence entry from which it is derived. What makes this database useful are not the entries themselves, but the analyses (e.g., multiple alignments, classification into subfamilies) that have been made on the data and that are available from the GCRDb database. It is a good example of a specialized database adding value by offering an analytical view on data that a universal sequence database is unable to provide. 

The specific information present in a PSSM, even when it is made from only two or three homologous sequences, particularly favors the similarity between the sequences aligned to compute it and can improve searching sensitivity dramatically. This is because constraints on each position in a multiple alignment become better defined as more exam-... 

Fig. 2. A multiple alignment of the seven globin sequences from Fig. 1. Identical residues are marked by stars and the approximate positions of the a helices are marked by boxes.

Until the late 1980s, most multiple alignments were carried out manually, using editors or word processors. This process is tedious and error prone, but it is facilitated greatly by dedicated alignment editors such as SEAVIEW (Galtier et al., 1996 and http //pbil.univ-lyonl. fr/software/... 

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