Transactions of the Nigerian Society of Biochemistry and Molecular Biology

Vol. 1, No. 1: 2011 pp. 5-12 (Printed in Nigeria) © 2011 Nigerian Society of Biochemistry and Molecular Biology

Biochemistry and Bioinformatics

Clement O. Bewaji
Department of Biochemistry, University of Ilorin, P. M. B. 1515, Ilorin, Kwara State, Nigeria

Introduction facing researchers in biomedical and pharmaceutical

Bioinformatics is the new academic disciplines is how to extract biologically useful
discipline which is an offshoot of Biochemistry. The information from millions of sequences. This is what
word “bioinformatics” suggests a bridge between the bioinformatics is supposed to address, using a
world of biology and that of information technology. multidisciplinary approach which combines computer
It is best defined as the branch of science which science, information theory and molecular biology.
applies computer technology and information theory Quite recently, attention has shifted to
to the study of biological sequence data comparative genomics and the study of single
Biochemistry was the first to serve as a nucleotide polymorphisms (SNPs). This has been
bridge between the physical and biological sciences. made possible by advances in genome sequencing
At the early stage, it was aptly named physiological technology (Alkan et al., 2009; Cai et al., 2004; Chen
chemistry which was later changed to biological et al., 2009; Conrad et al., 2010; Drmanal et al.,
chemistry (biology + some chemistry). Other 2010). Bioinformatics tools have also been deployed
disciplines quickly followed: biophysics, to the study of genomic variations among human
biomathematics and biocomputing -- the latter being races. This has been tagged the Human Haplotype
the favourite of crystallographers and those studying Project (International HapMap Consortium 2003,
three dimensional structures of macromolecules such 2005; Kidd et al., 2008; Kim et al.; 2009; Park et al.,
as proteins and nucleic acids. With the advent of 2010; Redon et al., 2006).
large-scale gene sequencing, a new scientific
discipline, known as computational molecular Information Storage and Retrieval
biology or bioinformatics, was born.
Protein and DNA sequences are being
The origin of bioinformatics can be traced to
determined in several laboratories around the world
the development by Sanger of a technique for the
on a continuous basis. This calls for the
sequencing of nucleic acids (Adamo, Filoteo et al.
establishments of banks for storing these data. Three
1995) (Sanger and Coulson, 1975). The original
big "banks" have emerged and are collaborating to
technique, devised in 1975, was subsequently
produce computerised DNA sequence databases.
improved upon and automated (Maxam and Gilbert,
These include:
1977; Sanger et al., 1977a). For this invention, and
for working out the first complete nucleotide
(1) the European Molecular Biology Laboratory
sequence for an organism (Sanger et al., 1977b),
(EMBL) in Cambridge, U.K.;
Sanger won a second Nobel prize in Chemistry which
(2) Genbank, based at the National Centre for
was awarded in 1980 (see Sanger, 1981 for the text of
Biotechnology Information (NCBI), a division
his Nobel lecture). He got his first Nobel prize in
of the National Library of Medicine, located on
1962 also for inventing the technique for the
the National Institutes of Health (NIH) campus
sequencing of proteins (Sanger and Tuppy, 1961;
in the USA; and
Sanger and Thompson, 1963). Sanger’s pioneering
(3) the DNA Database of Japan (DDBJ).
efforts paved the way for the sequencing of other
genomes, starting with the bacterial plasmid pBR322
These "banks" exchange information daily
(Sutcliffe, 1979).
and have agreed on common standards for DNA
Bioinformatics is still primarily concerned
sequence database entries. Each bank is responsible
with access to and analysis of the databases of
for collecting data from a different geographical area;
published gene and protein sequences. Increasingly,
e.g. EMBL covers Europe while Genbank covers
this is being augmented by similar methods applied
North America. The data contained in these banks
to databases of macromolecular structures and
can be accessed using the following web addresses:
genetic maps. At present, over one billion DNA and
protein sequences have been determined and
deposited in computerised databases. These
sequences contain a wealth of information hidden
within them, including protein structure, disease
mechanisms and drug target sites. The challenges

5
Transactions of the Nigerian Society of Biochemistry and Molecular Biology
Vol. 1, No. 1: 2011 pp. 5-12 (Printed in Nigeria) © 2011 Nigerian Society of Biochemistry and Molecular Biology

EMBL – http://www.ebi.ac.uk/ebi the database, the most popular being human (Homo
sapiens), baker’s yeast (Saccharomyces cerevisiae)
Genbank – http://www.ncbi.nlm.nih.gov and mouse (Mus musculus).
Information from various genomic projects
DDBJ – http://www.ddbj.nig.ac.jp are also deposited in different databases. Organisms
whose genes have been completely sequenced
The three banks are holding a tremendous include S. cerevisiae, Plasmodium falciparum,
amount of information. EMBL alone has over a Haemophilus influenzae, Mycoplasma genitalium and
billion nucleotide bases, with entries from the Human Escherichia coli (Table 1).
Genome Project (HGP) constituting 54% of the total.
More than 15,500 different species are represented in

Table 1: Some genomes that have been completely sequenced.

Organism Haploid Genome No. of Remarks

Size Chromosomes

Mycoplasma genitalium 580,000 1 Human parasite

Rickettsia prowazeki 1,112,000 1 Bacterium, Causative organism
of typhus
Borrelia burgdorferi 1,444,000 1 Lyme disease spirochaete
Methanococcus jannaschii 1,665,000 1 Thermophilic methanogenic
archaeon
Haemophilus influenzae 1,830,000 1 Bacterium, Human pathogen
Archaeoglobus fulgidus 2,178,000 1 Hyperthermophilic, sulphate-
reducing archaeon
Synechocystis sp. 3,573,000 1 Cyanobacterium
Mycobacterium tuberculosis 4,412,000 1 Causative organism of
tuberculosis
Escherichia coli 4,639,000 1 Bacterium, Human symbiotic
organism
Schizosaccharomyces pombe 13,800,000 3 Fission yeast
Saccharomyces cerevisiae 11,700,000 16 Baker’s yeast
Plasmodium falciparum 30,000,000 14 Protozoa, Causative organism of
malaria
Caenorhabditis elegans 97,000,000 6 Nematode worm
Drosophila melanogaster 137,000,000 4 Fruit fly
Arabidopsis thaliana 117,000,000 5 Flowering plant
Oryza sativa 430,000,000 12 Rice
Mus musculus 2,500,000,000 20 Mouse
Rattus norvegicus 2,600,000,000 21 Rat
Homo sapiens 3,200,000,000 23 Human

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Transactions of the Nigerian Society of Biochemistry and Molecular Biology
Vol. 1, No. 1: 2011 pp. 5-12 (Printed in Nigeria) © 2011 Nigerian Society of Biochemistry and Molecular Biology
Multiple Sequence Alignment
Bioinformatics is essentially a theoretical
discipline which attempts to make predictions about
biological functions from sequence data. It is also a
powerful tool in experimental design. The eventual
goal is to deduce protein structure and function
strictly from amino acid sequences. However all we
can do, at present, is to see whether the new
sequences being discovered are similar to sequences
whose structure and/or function are already known.
This is achieved by the use of sequence alignment
tools designed with various algorithms.
The sequence similarity of two polypeptides
or DNA molecules can be estimated quantitatively by
determining their number of aligned residues that are
identical. For example, human and dog cytochrome c
differ in 11 out of 104 residues in the molecule. They
are therefore 89% identical, i.e. [(104 – 11)/104] x
100. In the same way, it can be deduced that human
and baker’s yeast cytochrome c are [(104 – 45)/104]
x 100 = 57% identical. When determining the
percentage identity of two protein or DNA
molecules, the length of the shorter protein or DNA
is, by convention, used as the denominator.
Multiple sequence alignment is the process
of aligning two or more sequences with each other so
as to bring as many similar sequence characters
(nucleotides or amino acids) into register as possible.
The resulting alignments can be used for two
purposes: first, to find regions of similar sequence in
all of the sequences that define a conserved
consensus pattern or domain; and second, if the
alignment is particularly strong, to use the aligned
positions to try and derive the possible evolutionary
relationships among the sequences. When dealing
with a sequence of unknown function, the presence of
similar domains in several similar sequences implies
a similar biochemical function or structural fold that
may become the basis of further experimental
investigation. A group of similar sequences may
define a protein family which may share a common
biochemical function or evolutionary origin.
Similar proteins have been organized by
several laboratories into protein families. The
sequence families originally identified by Margaret
Dayhoff and colleagues became the basis of the PAM
matrices used for sequence comparisons (Dayhoff et
al., 1978). PAM stands for ‘percentage of acceptable
mutations’. Subsequently, Amos Bairoch identified a
large number of protein families and prepared a
database of amino acid patterns which is called the
PROSITE catalog and which define the active sites of
these proteins. These patterns are called MOTIFS.
Subsequently, Henikoff and Henikoff (1991) aligned
7
all these families, added more members from the
databases, and then defined conserved patterns of
amino acids called blocks. Blocks are present in all
members of the family and are approximately 4-60
amino acids long with no gaps or substitutions. The
BLOSUM (Blocks Substitution Matrix) amino acid
comparison tables were derived from these aligned
blocks. Common patterns of amino acids arising from
multiple sequence alignment have also been called
MOTIFS. These motifs may have more than one
amino acid at each position and may include gaps.
Once motifs have been defined, the sequence
databases may be searched for additional sequence
entries with the same motif.
Simultaneous alignment of three or more
sequences poses a difficult algorithmic problem but
programs to perform such alignments are now
available (for review, see Chan et al. 1992) and the
methods used have been compared (McLure et al.
1994). The method often used, especially for ten or
more sequences, is to first determine sequence
similarity between all pairs of sequences in the set.
Based on these similarities, various methods are then
used to cluster the sequences into the most related
groups or into a phylogenetic tree.
In the group approach, a consensus is
produced for each group and then used to make
further alignments between groups. Two examples of
programs using the grouping approach are the
program PIMA (Smith and Smith 1990) which
utilizes several novel alignment techniques and a
program described by Taylor (Taylor 1990), and
MAXHOM. (Sander & Schneider 1991).
The tree method uses the distance method of
phylogenetic analysis to arrange the sequences. The
two closest sequences are then aligned, and the
resulting consensus alignment is then aligned with
the next best sequence or cluster of sequences, and so
on, until an alignment is obtained which includes all
the sequences. The programs GCG PILEUP
developed by the Genetics Computer Group (GCG),
CLUSTAL W (Higgins and Sharp 1988), the ALIGN
set of programs (Feng and Doolittle1987) and the
MS/DOS program by Corpet (Corpet 1988) utilize
this method. A disadvantage to all these methods is
that the algorithm used is greedy since the alignment
is driven by the most alike sequences. An example of
using CLUSTAL to align a similar portion of four
hypothetical protein sequences is shown in Fig. 1.
Note that the CLUSTAL alignment produces a
consensus sequence at the bottom which shows
absolutely conserved positions with an "*", and
almost completely conserved positions with a":", but
the rest of the alignment is also remarkably similar.
Transactions of the Nigerian Society of Biochemistry and Molecular Biology
Vol. 1, No. 1: 2011 pp. 5-12 (Printed in Nigeria) © 2011 Nigerian Society of Biochemistry and Molecular Biology
A MAKEHASTEWHILETHEMANSHINES
B MAKEHASTEWHILETHEMENSHINE
C TAKEHASTEWHILETHEMANSHINES
D MAKEHASTEWHILETHEGIRLSSHINE
:****************. ......
Fig. 1: Alignment of some hypothetical proteins with
CLUSTAL W.
A novel algorithm MSA that reduces the
computational demands of dynamic programming
was used to align up to eight protein sequences
simultaneously (Lipman et al. 1989). Another
method which runs under the UNIX operating system
(Vingron and Argos 1991) aligns all possible pairs of
sequences to create a set of dot matrices, and the
matrices are then filtered sequentially to find motifs
which provide a starting point for sequence
alignment. MACAW is an interactive MS/DOS
computer program which searches for conserved
segments in a set of sequences, and then allows the
user to modify the alignments (Schuler et al. 1991).
Another set of UNIX programs for interactive
multiple sequence alignment by dot matrix analysis
and other alignment techniques has been developed
(Boguski et al. 1992).
The method most recently applied to
performing multiple sequence alignment is that of
using Hidden Markov Models (Baldi et al. 1994),
which has been shown to be more successful in
identifying motifs in protein families than several of
the aforementioned methods (McClure, 1995).
Multiple sequence alignments should be
done in a fashion that simultaneously minimizes the
number of changes needed during evolution to
generate the observed sequence variation. The
program TREEALIGN utilizes this approach (Hein
1990). In the program TREEALIGN (also named
ALIGN in the program versions), the author has
designed a method for performing the alignment and
the most parsimonious tree construction
simultaneously. To use this program requires the
assistance of an experienced UNIX programmer. The
method has two important features: (1) novel
applications of mathematical graph theory to perform
alignments between multiple sequences within a
phylogenetic tree, and (2) the use of distance rather
than similarity scores between sequences, as is
usually the case in aligning sequences by dynamic
programming methods. The initial steps are similar to
other multiple sequence alignment methods, except
for the use of a distance scale, i.e. the sequences are
aligned pair-wise and the resulting distance scores are
used sequentially to produce a tree, which is
8
rearranged as more sequences are added. The
sequences are then re-aligned so that the same tree
can be produced by maximum parsimony. Finally,
the tree is rearranged to maximize parsimony. The
advantage of this method is the use of phylogenetic
analysis to improve the multiple sequence alignment.
A disadvantage is that use of the maximum
parsimony criterion does not produce statistically
testable models and favours phylogenetic trees with
an increased number of nodes and short branches.
Blocks Substitution Matrices for Protein Sequence
Comparisons (BLOSUM).
The BLOSUM substitution matrices are
used for scoring protein sequence alignments
(Henikoff and Henikoff, 1992). The matrix values are
based on the observed amino acid substitutions in a
large set of approximately 2000 conserved amino
acid patterns, called blocks. These blocks have been
found in a database of protein sequences representing
over 500 groups of related proteins (Henikoff and
Henikoff 1992), and act as signatures of these protein
families. The blosum matrices are based on an
entirely different principle and a much larger data set
than the Dayhoff PAM matrices, which are derived
from the observed rate of mutation during the
predicted evolutionary changes in a smaller number
of protein families . The Blosum62 matrix, explained
below, detected more distant relationships in a
BLAST search, and produced an alignment of
diverged proteins more in agreement with three-
dimensional structures, than did the corresponding
PAM60 matrix (Henikoff and Henikoff 1992,
1993).The Blosum62 matrix is, therefore, highly
recommended for sequence alignment and database
searching.
To prepare the Blosum matrices, the
sequences of the individual proteins in each of the
500 families were aligned in the regions defined by
the blocks. Each column in the aligned sequences
then provided a set of possible amino acid
substitutions. Note that the probability of change
from amino acid A to amino acid B is the same as the
probability of the reverse change from B to A in this
analysis. The types of substitutions were then scored
for all aligned patterns in the database. More
common substitutions should represent a closer
relationship between two amino acids in related
proteins, and thus receive a more favourable score in
sequence alignment. Conversely, rare substitutions
should be less favoured. This procedure, however,
can lead to an over-representation of amino acid
substitutions which occur in the most closely related
members of the protein families. To reduce this
dominant contribution from the most alike proteins,
the sequences of these proteins were grouped
Transactions of the Nigerian Society of Biochemistry and Molecular Biology
Vol. 1, No. 1: 2011 pp. 5-12 (Printed in Nigeria) © 2011 Nigerian Society of Biochemistry and Molecular Biology
together into one sequence before scoring the amino
acid substitutions in the aligned blocks. The amino
acid changes within these clustered sequences were
then averaged. Patterns which were 60% identical
were grouped together to make one substitution
matrix called BLOSUM60, and those 80% alike to
make another matrix called BLOSUM80, and so on.
As the clustering percentage was increased,
the ability of the resulting matrix to distinguish actual
from chance alignments, defined as the relative
entropy or average information content per residue
pair, also increased. However, at the same time, the
dominance effect of the more alike proteins also
increased and biased the matches. BLOSUM62
(Table 2) represents a balance between information
content and match bias and is the favored matrix that
is best able to predict alignments among all protein
families.
The amino acids in the table are grouped
according to the chemistry of the side group: C
(sulfhydryl), STPAG (small hydrophilic), NDEQ
(acid, acid amide and hydrophilic), HRK (basic),
MILV (small hydrophobic) and FYW (aromatic).
Each entry is the actual frequency of occurrence of
the amino acid pair in the blocks database, clustered
at the 62% level, divided by the expected probability
of occurrence. The expected value is calculated from
the frequency of occurrence of each of the two
individual amino acids in the blocks database, and
provides a measure of a chance alignment of the two
amino acids. The actual/expected ratio is expressed
as a log odds score in so-called half bit units,
obtained by converting the ratio to a logarithm to the
base 2, and then multiplying by 2. A zero score
means that the frequency of the amino acid pair in the
database was as expected by chance, a positive score
that the pair was found more often than by chance,
and a negative score that the pair was found less
often than by chance. The accumulated score of an
alignment of several amino acids in two sequences
may be obtained by adding up the respective scores
of each individual pair of amino acids.
The highest scoring matches are between
amino acids which are in the same chemical group
and the very highest scoring matches are for cysteine-
cysteine matches and for matches among the
aromatic amino acids. A similar variation is seen in
the PAM matrices. Compared to the PAM160 matrix,
however, the BLOSUM62 matrix gives a more
positive score to mismatches with the rare amino
acids e.g. cysteine, a more positive score to
mismatches with hydrophobic amino acids, but a
more negative score to mismatches with hydrophilic
amino acids (Henikoff and Henikoff 1992).
9
Sequence alignments based on Bayesian Statistics
There is need for a method of finding
sequence alignment that examines all possible
alignments and does not depend on scoring matrix
and gap penalties. To solve this problem, the
following algorithms/properties have been
considered:
 dynamic programming provides many different
possible alignments and may have many
alignments with about the same score
 each combination of matrix/penalty combination
gives a different alignment and alignment score
 for protein alignments, the gaps should only be
in certain regions corresponding to loops on the
outside of the 3D structure: gaps should not
occur in regions corresponding to the core of the
3D structure - a tightly packed hydrophobic
environment
 instead of looking for alignments with gaps -
there is another algorithm for finding ungapped
regions with matches and mismatches - these are
called blocks - they might correspond to the a
helices and b strands in the protein core.
The Need For A Bioinformatics Curriculum
Bioinformatics will continue to influence the
way we think and the way we do science. Students of
Biochemistry, Genetics or Molecular Biology will
need to know more about the new discipline if they
intend to get employment in the pharmaceutical or
biotechnology industries. We are gradually
approaching the era of personalised medicine (Wang
et al., 2008; Wheeler et al., 2008; Bodmer and
Bonilla, 2008).
This raises the question of developing a
curriculum in Bioinformatics. Undergraduate and
postgraduate students as well as researchers need a
basic understanding of the Internet and how to search
for appropriate information on it. This means that
universities must invest in making a large number of
networked PCs available for this purpose. This is a
sine qua non for picking up the skill for browsing the
web which is essential in gaining access to biological
sequence databases.
Teaching bioinformatics will be more
difficult to achieve with our current educational
philosophy. This is because our current practice in
curriculum design treats the physical and biological
sciences as alternatives. There is need for all science
students to take courses in mathematics, computer
science and biology up to 200 level in the
universities.
Transactions of the Nigerian Society of Biochemistry and Molecular Biology
Vol. 1, No. 1: 2011 pp. 5-12 (Printed in Nigeria) © 2011 Nigerian Society of Biochemistry and Molecular Biology

Table 2: The BLOSUM62 Amino Acid Substitution Matrix.

C S T P A G N D E Q H R K M I L V F Y W

C 9 -1 -1 -3 0 -3 -3 -3 -4 -3 -3 -3 -3 -1 -1 -1 -1 -2 -2 -2

S -1 4 1 -1 1 0 1 0 0 0 -1 -1 0 -1 -2 -2 -2 -2 -2 -3

T -1 1 4 1 -1 1 0 1 0 0 0 -1 0 -1 -2 -2 -2 -2 -2 -3

P -3 -1 1 7 -1 -2 -1 -1 -1 -1 -2 -2 -1 -2 -3 -3 -2 -4 -3 -4

A 0 1 -1 -1 4 0 -1 -2 -1 -1 -2 -1 -1 -1 -1 -1 -2 -2 -2 -3

G -3 0 1 -2 0 6 -2 -1 -2 -2 -2 -2 -2 -3 -4 -4 0 -3 -3 -2

N -3 1 0 -2 -2 0 6 1 0 0 -1 0 0 -2 -3 -3 -3 -3 -2 -4

D -3 0 1 -1 -2 -1 1 6 2 0 -1 -2 -1 -3 -3 -4 -3 -3 -3 -4

E -4 0 0 -1 -1 -2 0 2 5 2 0 0 1 -2 -3 -3 -3 -3 -2 -3

Q -3 0 0 -1 -1 -2 0 0 2 5 0 1 1 0 -3 -2 -2 -3 -1 -2

H -3 -1 0 -2 -2 -2 1 1 0 0 8 0 -1 -2 -3 -3 -2 -1 2 -2

R -3 -1 -1 -2 -1 -2 0 -2 0 1 0 5 2 -1 -3 -2 -3 -3 -2 -3

K -3 0 0 -1 -1 -2 0 -1 1 1 -1 2 5 -1 -3 -2 -3 -3 -2 -3

M -1 -1 -1 -2 -1 -3 -2 -3 -2 0 -2 -1 -1 5 1 2 -2 0 -1 -1

I -1 -2 -2 -3 -1 -4 -3 -3 -3 -3 -3 -3 -3 1 4 2 1 0 -1 -3

L -1 -2 -2 -3 -1 -4 -3 -4 -3 -2 -3 -2 -2 2 2 4 3 0 -1 -2

V -1 -2 -2 -2 0 -3 -3 -3 -2 -2 -3 -3 -2 1 3 1 4 -1 -1 -3

F -2 -2 -2 -4 -2 -3 -3 -3 -3 -3 -1 -3 -3 0 0 0 -1 6 3 1

Y -2 -2 -2 -3 -2 -3 -2 -3 -2 -1 2 -2 -2 -1 -1 -1 -1 3 7 2

W -2 -3 -3 -4 -3 -2 -4 -4 -3 -2 -2 -3 -3 -1 -3 -2 -3 1 2 11

Source: Henikoff and Henikoff (1992).

Students will need to be exposed to the
various sequence databases available, the genomic
projects that have been completed and how to
perform simple analysis on a sequence, i.e. how to
compare a new sequence against a database to
determine whether similar sequences exist, and to
make predictions about the function of the new
sequence. Anyone who can acquire these skills will
be the hottest in demand in a global market place
which cuts across the Atlantic.

10
Transactions of the Nigerian Society of Biochemistry and Molecular Biology
Vol. 1, No. 1: 2011 pp. 5-12 (Printed in Nigeria) © 2011 Nigerian Society of Biochemistry and Molecular Biology
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