Download From Genes to Proteins

Biology at a glance
Aplicações biomédicas em plataformas
computacionais de alto desempenho
Aplicaciones biomédicas sobre plataformas gráficas de altas prestaciones
Biomedical applications in High performance computing platforms
Oswaldo Trelles, PhD
University of Malaga
The fundamentals of life are stored in the material that constitute organisms but specially in the
information that governs their organization, development, proliferation, identity and evolution. This
section surveys the sources of information in living organisms and their relationships
O.Trelles, PhD
Cells, DNA,
chromosomes,
genes and proteins
O.Trelles, PhD
All living organisms are made of cells
All cells contains all the genetic information (except germinal)
Prokariote (without nucleus, one circular chromosome, few
intergenic regions, etc)
Eukaryote: other organels (inherited from females) with additional
genetic material, long intergenic regions, …
O.Trelles, PhD
The DNA carries the genetic information
The Genetic information that living organisms transmit from parents to
progeny is coded in the ADN (deoxyribonucleic acid) stored in the
cell (nucleus in eukaryotes).
DNA is a double stranded long linear polymer of nucleotides:{ A,C,G,T}
Complementary bases allows replication and transcription
O.Trelles, PhD
The full genome of the organism is present in every cell of the
organism, except in the germinal or sexual cell.
A “DNA sequence” is represented as a string in a
fourth letter alphabet of DNA-nucleotides.
A “protein sequence” refers to the consecutive
string of the 20 letters amino acid alphabet.
The genome is the full genetic endowment
Size: few thousands of bases some GB
O.Trelles, PhD
The DNA is organised in chromosomes in the cell.
The number of chromosomes differs along organisms
22 of the 23 pairs of human chromosomes are equal in
size and shape each couple- the last pair depends on
the gender:
The human chromosome pair number 23 is different in
males (X-Y) and females (X-X)
Germinal cells have half of the genetic information
During fecundation the new organism receives the pair.
Neither the number nor the size of the genome is related
to the organism complexity.
Mutations can occur during cell division
Mutations substantial impacts on evolution
O.Trelles, PhD
The main function of genes is to carry out the instructions to
synthetize a protein (or even several proteins)
By unwinding the DNA its nucleotide composition is exposed in a paired complementary
double helix. The sequence is typically read in the 5 'end (that will later be the amino
terminus in the protein) to the 3' (carboxyl) and as is usually stored in databases or flat
text files. In the figure above, the DNA strand would read "ACGTTGA .... ACAG ..."
O.Trelles, PhD
The main function of genes is to carry out the instructions to
synthetize a protein (or even several proteins)
Genes code for proteins: coding regions.
Proteins are also long linear molecules
In the same order than DNA corresponding
bases
Every group of 3 bases (codon) codes a
particular aminoacid: Genetic code
Each gene consist of thousand of bases and
codes for one (or several alternative) protein.
Proteins includes thousand of enzymes, which
control all the chemical reactions taking place in
the body, producing growth, movement,
behavior, digestion, and all other life processes;
controlling every aspect of living things
O.Trelles, PhD
Central Dogma of molecular biology
The central dogma of molecular biology
states:
(1) DNA carries the genetic information of
organisms and replicates during cell
division to allow each daughter cell to
contain
a
full
complement
of
chromosomes.
(2) The genetic information in the DNA is
used
in
a
process
called
transcription
to
produce
a
complementary one-strand messenger
of mRNA
(3) mRNA is interpreted (translation) in the
ribosomes using the genetic-code to
produce a protein.
Replication
DNA
Trascription
RNA
Translation
Protein
O.Trelles, PhD
From
Genes to
Proteins
Genes contains the instructions for protein synthesis. That instructions are translated by the
cellular machinery using the so called genetic code that translate each consecutive codon
(DNA triple) into an specific amino acid
O.Trelles, PhD
Messenger RNA contains only coding DNA
Protein synthesis start with a copy of
one of the DNA strands into RNA
inside the cellular nucleus. This RNA is
spliced to remove the introns (mature
mRNA).
To ribosomes
Small signals for starting (donors) of
introns and exons and ending points
(acceptors) are used to identify the
right cutting position, including the stop
signals for ending the translation.
O.Trelles, PhD
The Genetic code establish the correspondence between each
codon (3 consecutive DNA bases) and a given amino acid
The order of the AA in the protein chain
is the same as the order of their
corresponding codons in the DNA.
Translation is the mechanism by
which the sequence of codons (DNA)
produce a sequence of amino acids
(proteins)
Each combination of 3 nucleotides
determine a specific amino acid. That
correspondence is called the Genetic
Code.
Thus, the AAA codon codes for the
Lysine (K) amino acid, while, the TGC
codes for a Cysteine (C) See table
Noteworthy observe, there are only 20 amino acids (and 3 stop signals) but up to 64 different codons (from AAA to TTT). When
the initial base of a codon is unknown, there are 6 different possible coding chains (or ORF, open reading frames).
O.Trelles, PhD
Although the DNA is extemelly important,
organisms are made of proteins.
The main function of DNA is to contain the instructions
to drive the synthesis of proteins
Organisms are made of proteins (bones, muscles,
nervous…
Protein function is associated with their 3D shape
O.Trelles, PhD
Structural levels of proteins
Primary structure
The sequence of AA
Secondary structure:
alpha -helix, ßeta-strand
Tertiary structure : 3D
& turns
spatial conformation
Quaternary structure
Molecular complexes.
Potassium channel: gate to regulate the
ions K+ in (rat & human brain:6 molecules
O.Trelles, PhD
Structural Protein datases (PDB)
Protein sequences: UniProt
HEADER
TITLE
TITLE
COMPND
COMPND
COMPND
SOURCE
SOURCE
KEYWDS
EXPDTA
AUTHOR
AUTHOR
REVDAT
SPRSDE
JRNL
JRNL
JRNL
JRNL
JRNL
REMARK
REMARK
REMARK
REMARK
REMARK
DBREF
DBREF
SEQRES
SEQRES
HELIX
HELIX
HELIX
TURN
SSBOND
SSBOND
SSBOND
CRYST1
ORIGX1
SCALE1
SCALE2
MODEL
ATOM
ATOM
ATOM
HORMONE
08-OCT-96
2HIU
NMR STRUCTURE OF HUMAN INSULIN IN 20% ACETIC ACID,
2 ZINC-FREE, 10 STRUCTURES
MOLECULE: INSULIN;
2 CHAIN: A, B;
3 BIOLOGICAL_UNIT: HETERODIMER
ORGANISM_SCIENTIFIC: HOMO SAPIENS;
2 ORGANISM_COMMON: HUMAN
INSULIN, HORMONE, GLUCOSE METABOLISM
NMR, 10 STRUCTURES
Q.X.HUA,S.N.GOZANI,R.E.CHANCE,J.A.HOFFMANN,B.H.FRANK,
2 M.A.WEISS
1
01-APR-97 2HIU
0
01-APR-97 2HIU
1HIU
AUTH
Q.X.HUA,S.N.GOZANI,R.E.CHANCE,J.A.HOFFMANN,
AUTH 2 B.H.FRANK,M.A.WEISS
TITL
STRUCTURE OF A PROTEIN IN A KINETIC TRAP
REF
NAT.STRUCT.BIOL.
V.
2
129 1995
REFN
ASTM NSBIEW US ISSN 1072-8368
2024
1 NUMBER OF NON-HYDROGEN ATOMS USED IN REFINEMENT.
1
PROTEIN ATOMS
: 785
1
NUCLEIC ACID ATOMS
: 0
1
HETEROGEN ATOMS
: 0
1
SOLVENT ATOMS
: 0
2HIU A
1
21 SWS
P01308
INS_HUMAN
90
110
2HIU B
1
30 SWS
P01308
INS_HUMAN
25
54
1 A
21 GLY ILE VAL GLU GLN CYS CYS THR SER ILE CYS SER LEU
2 A
21 TYR GLN LEU GLU ASN TYR CYS ASN
1
1 ILE A
2 THR A
8 1
2
2 LEU A
13 TYR A
19 1
3
3 SER B
9 CYS B
19 1
1 T1 GLY B 20 GLY B 23
1 CYS A
6
CYS A
11
2 CYS A
7
CYS B
7
3 CYS A
20
CYS B
19
1.000
1.000
1.000 90.00 90.00 90.00 P 1
1
1.000000 0.000000 0.000000
0.00000
1.000000 0.000000 0.000000
0.00000
0.000000 1.000000 0.000000
0.00000
1
1 N
GLY A
1
-6.132
6.735
1.016 1.00 0.00
2 CA GLY A
1
-4.686
6.753
1.376 1.00 0.00
3 C
GLY A
1
-3.864
6.149
0.235 1.00 0.00
PDB: Protein Data Bank
UniProt:Universal Protein
Resource
-
UniProtKB / Swiss-Prot
-
UniProtKB/TrEMBL?
7
7
11
N
C
C
O.Trelles, PhD
Data growth rates
O.Trelles, PhD
Metabolic Pathways: KEGG db
O.Trelles, PhD
Expresion de
genes
Las células portan el ADN y los genes con instrucciones para sintetizar proteínas. Cada
proteína cumple una determinada función, sin embargo no trabajan de forma aislada sino
interactuando y formando compuestos entre ella como respuesta al entorno o a sus cambios.
O.Trelles, PhD
The biological response
Protein levels defines the cellular state
Changes in the proteins levels arise as
response to stimuly
To increase or decrease the protein
levels the cellular machinery activate /
de-activate the corresponding genes
Measuring the levels of proteins in a
experimental condition provides information
on the mechnism of response
O.Trelles, PhD
The biological response
Expression
level
Different proteins have a particular concentration
In different organs
Proteins
catalogue
A control situation is defined
O.Trelles, PhD
The “transcriptomics” data set
Intensity values for several
control and target individuals (in
the colmuns) for several genes (in
the rows)
O.Trelles, PhD
Applications
Changes are associated with the
biological response; thus:
- Biological markers
- Identify pathologies
- Design treatment protocols
- Obtain a desired behavior in the
organism:
- Better color, flavor,
phenotype
- Resistance to pathogens,
stress …
O.Trelles, PhD
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O.Trelles, PhD