computational biology: molecular biology primer figures and slides taken from various sources on the...
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Computational Biology:Molecular Biology Primer
Figures and slides taken from various sources on the internetincluding, www.bioalgorithms.info (sources mostly acknowledged)
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Cells
• Fundamental working units of every living system. • Every organism is composed of one of two radically different types of cells: prokaryotic cells or eukaryotic cells.• Prokaryotes and Eukaryotes are descended from the same primitive
cell. – All extant prokaryotic and eukaryotic cells are the result of a total of
3.5 billion years of evolution.
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Evolutionary Tree of Life
Njsas.org
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Bacterial Cell (Prokaryote)
Uccs.edu
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Animal Cell (Eukaryotic)
Faculty.southwest.tn.edu
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Prokaryotes and Eukaryotes
Prokaryotes Eukaryotes
Single cell Single or multi cell
No nucleus Nucleus
No organelles Organelles
One piece of circular DNA Chromosomes
No mRNA post transcriptional modification
Exons/Introns splicing
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Prokaryotic and Eukaryotic CellsChromosomal differences
Prokaryotes The genome of E.coli contains
amount of 4X106 base pairs > 90% of DNA encode protein
Lacks a membrane-bound nucleus. Circular DNA and supercoiled domain
Histones are unknown
Eukaryotes The genome of yeast cells contains 1.35x107 base pairs A small fraction of the total DNA
encodes protein. Many repeats of non-coding
sequences All chromosomes are contained in
a membrane bound nucleus DNA is divided between two or
more chromosomes A set of five histones
DNA packaging and gene expression regulation
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Cells: Information and Machinery
• Cells store all information to replicate itself– Human genome is around 3 billions base pair long– Almost every cell in human body contains same
set of genes– But not all genes are used or expressed by those
cells
• Machinery:– Collect and manufacture components– Carry out replication– Kick-start its new offspring(A cell is like a car factory)
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Some Terminology
• Genome: an organism’s genetic material
• Gene: a discrete units of hereditary information located on the chromosomes and consisting of DNA.
• Genotype: The genetic makeup of an organism
• Phenotype: the physical expressed traits of an organism
• Nucleic acid: Biological molecules(RNA and DNA) that allow organisms to reproduce;
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All Life depends on 3 critical molecules• DNAs
– Hold information on how cell works
• RNAs– Act to transfer short pieces of information to different parts of
cell
– Provide templates to synthesize into protein
• Proteins– Form enzymes that send signals to other cells and regulate gene
activity
– Form body’s major components (e.g. hair, skin, etc.)
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Cells & DNA
Ogm-info.com
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DNA: The Code of Life
• The structure and the four genomic letters code for all living organisms • Adenine, Guanine, Thymine, and Cytosine which pair A-T and C-G on
complimentary strands.
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Superstructure: DNA and Chromosome
Lodish et al. Molecular Biology of the Cell (5th ed.). W.H. Freeman & Co., 2003.
(length of 1 bp)(number of bp per cell)(number of cells in the body)(0.34 × 10-9 m)(3 × 109)(1013) = 1.0 × 1013 meters (35 trips to Sun!)
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Chromosomes
Organism Number of base pair number of Chromosomes
---------------------------------------------------------------------------------------------------------
Prokayotic
Escherichia coli (bacterium) 4x106 1
Eukaryotic
Saccharomyces cerevisiae (yeast) 1.35x107 17
Drosophila melanogaster(insect) 1.65x108 4
Homo sapiens(human) 2.9x109 23
Zea mays(corn) 5.0x109 10
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Building Blocks of Biological Systems: nucleotides and amino acids
DNA (nucleotides, 4 types): information carrier/encoder.RNA: bridge from DNA to protein.Protein (amino acids, 20 types): action molecules.
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Four types of nucleic acids of DNADNA
Note that A pairs with T; and G pairs with C.
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Primary Structure of DNA
atgaatcgta ggggtttgaa cgctggcaat acgatgactt ctcaagcgaa cattgacgac ggcagctgga aggcggtctc cgagggcgga ……
• Unbranched polymer
• Sequence of nucleotide bases
• Double stranded
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DNA, continued• DNA has a double helix
structure which composed of – sugar molecule– phosphate group– and a base (A,C,G,T)
• DNA always reads from 5’ end to 3’ end for transcription replication 5’ ATTTAGGCC 3’3’ TAAATCCGG 5’
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Processes
• Replication of DNA
• Transcription of gene (DNA) to messenger RNA (mRNA)
• Translation of mRNA into proteins
• Folding of proteins into 3D from
• Biochemical or structural functions of proteins
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DNA, RNA, and the Flow of Information
TranslationTranscription
Replication
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Overview of DNA to RNA to Protein
• A gene is expressed in two steps1) Transcription: RNA synthesis2) Translation: Protein synthesis
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© 1999 The International Herpes Management Forum, all rights reserved.
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RNA• RNA is similar to DNA chemically. It is usually only a
single strand. T(hyamine) is replaced by U(racil)
• Some forms of RNA can form 3D structures by “pairing up” with itself.
DNA and RNA
can pair with
each other.
http://www.cgl.ucsf.edu/home/glasfeld/tutorial/trna/trna.gif
tRNA linear and 3D view:
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RNA, continued• Several types exist, classified by function
• mRNA – this is what is usually being referred to when a Bioinformatician says “RNA”. This is used to carry a gene’s message out of the nucleus.
• tRNA – transfers genetic information from mRNA to an amino acid sequence
• rRNA – ribosomal RNA. Part of the ribosome which is involved in translation.
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Terminology for Splicing• Exon: A portion of the gene that appears in
both the primary and the mature mRNA transcripts.
• Intron: A portion of the gene that is transcribed but excised prior to translation.
• Lariat structure: The structure that an intron in mRNA takes during excision/splicing.
• Spliceosome: A organelle that carries out the splicing reactions whereby the pre-mRNA is converted to a mature mRNA.
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Definition of a Gene
• Regulatory regions: up to 50 kb upstream of +1 site
• Exons: protein coding and untranslated regions (UTR)1 to 178 exons per gene (mean 8.8)8 bp to 17 kb per exon (mean 145 bp)
• Introns: splice acceptor and donor sites, junk DNAaverage 1 kb – 50 kb per intron
• Gene size: Largest – 2.4 Mb (Dystrophin). Mean – 27 kb.
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Splicing
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Splicing and other RNA processing
• In Eukaryotic cells, RNA is processed between transcription and translation.
• This complicates the relationship between a DNA gene and the protein it codes for.
• Sometimes alternate RNA processing can lead to an alternate protein as a result. This is true in the immune system.
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Splicing (Eukaryotes)• Unprocessed RNA is
composed of Introns and Extrons. Introns are removed before the rest is expressed and converted to protein.
• Sometimes alternate splicings can create different valid proteins.
• A typical Eukaryotic gene has 4-20 introns. Locating them by analytical means is not easy.
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Translation: Proteins• Codon: The sequence of 3 nucleotides in DNA/RNA that
encodes for a specific amino acid. • mRNA (messenger RNA): A ribonucleic acid whose sequence is
complementary to that of a protein-coding gene in DNA.• Ribosome: The organelle that synthesizes polypeptides under the
direction of mRNA• rRNA (ribosomal RNA):The RNA molecules that constitute the
bulk of the ribosome and provides structural scaffolding for the ribosome and catalyzes peptide bond formation.
• tRNA (transfer RNA): The small L-shaped RNAs that deliver specific amino acids to ribosomes according to the sequence of a bound mRNA.
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© 1999 The International Herpes Management Forum, all rights reserved.
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Purpose of tRNA
• The proper tRNA is chosen by having the corresponding anticodon for the mRNA’s codon.
• The tRNA then transfers its aminoacyl group to the growing peptide chain.
• For example, the tRNA with the anticodon UAC corresponds with the codon AUG and attaches methionine amino acid onto the peptide chain.
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Translation: Universal Genetic Code
• Translation form nucleotide code to amino acid code.
atgaatcgta ggggtttgaa cgctggcaat acgatgactt ctcaagcgaa cattgacgac ggcagctgga aggcggtctc cgagggcgga ……
MNRRGLNAGNTMTSQANIDDGSWKAVSEGG …
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Uncovering the code
• Scientists conjectured that proteins came from DNA; but how did DNA code for proteins?
• If one nucleotide codes for one amino acid, then there would be 41 amino acids
• However, there are 20 amino acids, so at least 3 bases codes for one amino acid, since 42 = 16 and 43 = 64– This triplet of bases is called a “codon”
– 64 different codons and only 20 amino acids means that the coding is degenerate: more than one codon sequence code for the same amino acid
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Genetic Code
uccs.edu
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Translation
• The process of going from RNA to polypeptide.
• Three base pairs of RNA (called a codon) correspond to one amino acid based on a fixed table.
• Always starts with Methionine and ends with a stop codon
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Proteins: Workhorses of the Cell• 20 different amino acids
– different chemical properties cause the protein chains to fold up into specific three-dimensional structures that define their particular functions in the cell.
• Proteins do all essential work for the cell– build cellular structures– digest nutrients – execute metabolic functions– Mediate information flow within a cell and among
cellular communities. • Proteins work together with other proteins or nucleic acids as
"molecular machines" – structures that fit together and function in highly
specific, lock-and-key ways.
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Sequence of Amino Acids: Protein
• Unbranched polymer
• Peptide backbone
• Twenty side chain types
• 3D structure the key
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Amino Acid
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Polypeptide Chain
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Torsion Angles
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Protein Primary Structure
• Unbranched polymer
• 20 side chains
MNRRGLNAGNTMTSQANIDDGSWKAVSEGG …
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3D: Higher Order Protein Structures
• Higher order structures– Secondary: local in sequence– Tertiary: 3D fold of one polypeptide chain– Quaternary: Chains packing together
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Protein Structure• Proteins are composed of twenty
amino acids
• Amino acids are composed of a
central carbon atom attached to four
groups of atoms.
• Amino acids (AA) combine in
sequence to form a polymer
(polypeptide chain).
• A chain folds into a specific 3D
shape by the laws of nature.
• A protein is made up of one or more
chains.
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Protein Structure Hierarchy
Primary structure: The linear sequence of amino acids comprising a protein:
AGVGTVPMTAYGNDIQYYGQVT…AGVGTVPMTAYGNDIQYYGQVT…Secondary structure: local ordered sub-structures two common types: α-Helix and β-Sheet
Beta sheet
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Protein Structure HierarchyTertiary structure:
"global" folding of a single chain in 3D form.
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1BGS-E (BARNASE) 1BGS-A (BARSTAR)
1BGS-AE
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Protein Folding
• Proteins the action molecules of life
• 3D Structure critical to function
• Many protein sequences fold spontaneously to native 3D fold
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Protein Folding• The structure that a
protein adopts is vital to it’s chemistry
• Its structure determines which of its amino acids are exposed carry out the protein’s function
• Its structure also determines what substrates it can react with
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Protein Folding
•A folding pathway is defined as a time sequence of folding events.
•If protein folding were a random process, folding would be very slow.
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Folding Pathways
•Early events in the folding pathway speed folding by eliminating other possible pathways.
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Protein FunctionsBinding Catalysis
Switching Structural Proteins
(petsko & ringe; protein structure & function)
initiate transcription bind oxygen
GDP-bound: Off GTP-bound: OnMuscle Fibers
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Protein Functions• Proteins as molecular machines
– Change shape, open/close, twist/turn
• Proteins as catalysts– enzymes — proteins that act as catalysts — make life possible
• Proteins work together in pathways — sequences of chemical reactions — to perform a wide variety of functions
• Metabolism — mediate chemical reactions (oxygen to burn food). • Signaling — Signaling pathways within a cell & between cells. • Regulation — control reactions; gateways in cellular membranes. • Cellular structure — define cell shape and form. • Transportation — move other proteins, oxygen, sugar, nutrients and wastes
into and around cells. • Movement - contract muscles and move cells. • DNA Transcription — turn genes on and off. • Immune System Functions - identify germs and other foreign substances
and mark them for destruction.
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Systems Biology
• Study of Biological Networks– Gene Networks– Protein Networks– Metabolic Networks– Signaling Networks
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Genomics to Proteomics
Gene mRNA Protein
transcription translation
Genome Transcriptome Proteome
static dynamic
One gene Many transcripts Many proteins
(alternative splicing) (post-translational modifications)
traditional
new
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Proteomics
• The Proteome is the complete set of proteins in the cell under a set of conditions. It is dynamic and complex, and characterized in terms of:– Structure – shape, electrostatics– Abundance – protein expression– Localization - subcellular location– Modifications – post translational modifications – Interactions – protein-protein interactions (interactome)
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Protein Interaction Network(Raul et al, Nature, Oct 2005)
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Metabolic Network
Scb.su.se
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Signaling Pathways: Control Gene Activity
• Instead of having brains, cells make decision through complex networks of chemical reactions, called pathways– Synthesize new materials– Break other materials down for spare parts– Signal to eat or die
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Example of cell signaling
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Signaling Networks
Gene-regulation.com
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Why Computational Biology or Bioinformatics?
• Computational Biology is the combination of biology and computing.
• DNA sequencing technologies have created massive amounts of information that can only be efficiently analyzed with computers.
• So far 70 species sequenced– Human, rat chimpanzee, chicken, and many others.
• As the information becomes ever so larger and more complex, more computational tools are needed to sort through the data. – Computational Biology to the rescue!!!
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What is Computational Biology?
• Computational Biology is generally defined as the analysis, prediction, and modeling of biological data with the help of computers
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Bio-Information
• Since discovering how DNA acts as the instructional blueprints behind life, biology has become an information science
• Now that many different organisms have been sequenced, we are able to find meaning in DNA through comparative genomics, not unlike comparative linguistics.
• Slowly, we are learning the syntax of DNA
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Sequence Analysis
• Some algorithms analyze biological sequences for patterns– RNA splice sites– ORFs– Amino acid propensities in a protein– Conserved regions in
• AA sequences [possible active site]• DNA/RNA [possible protein binding site]
• Others make predictions based on sequence– Protein/RNA secondary structure folding
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Human Genome Composition
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It is Sequenced, What’s Next?• Tracing Phylogeny
– Finding family relationships between species by tracking similarities between species.
• Gene Annotation (cooperative genomics)
– Comparison of similar species.• Determining Regulatory Networks
– The variables that determine how the body reacts to certain stimuli.
• Proteomics
– From DNA sequence to a folded protein.
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Modeling
• Modeling biological processes tells us if we understand a given process
• Because of the large number of variables that exist in biological problems, powerful computers are needed to analyze certain biological questions
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Protein Modeling
• Quantum chemistry imaging algorithms of active sites allow us to view possible bonding and reaction mechanisms
• Homologous protein modeling is a comparative proteomic approach to determining an unknown protein’s tertiary structure
• Predictive tertiary folding algorithms are a long way off, but we can predict secondary structure with ~80% accuracy.
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Regulatory Network Modeling
• Micro array experiments allow us to compare differences in expression for two different states
• Algorithms for clustering groups of gene expression help point out possible regulatory networks
• Other algorithms perform statistical analysis to improve signal to noise contrast
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Systems Biology Modeling
• Predictions of whole cell interactions.– Organelle processes, expression modeling
• Currently feasible for specific processes (eg. Metabolism in E. coli, simple cells)
Flux Balance Analysis
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Example: Mining the Omics Graph
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The future…
• Computational Biology and Bioinformatics is still in it’s infancy
• Much is still to be learned about how proteins can manipulate a sequence of base pairs in such a peculiar way that results in a fully functional organism.
• How can we then use this information to benefit humanity without abusing it?