BiologyOverview.ppt

CS 6463: An overview of Molecular Biology 1

21st Century = Biotech Century

• Completion of human genome• High-throughput microarray and similar devices• Cloning• Genetic engineering• Computational power

Everyone is moving towards Biotech

Explosive growth of biological data

Biology is becoming more computational intensive. High throughput bioinformatics, Lots of data The Molecular Biology Database Collection: 2005 update

Small excerpt from the A's: AARSDB: Aminoacyl-tRNA synthetase sequences ABCdb: ABC transporters AceDB: C. elegans, S. pombe, and human sequences

and genomic information ACTIVITY: Functional DNA/RNA site activity ALFRED: Allele frequencies and DNA polymorphisms

Opportunities for CS

Possibilities for CS contributions Data integration problem Data extraction from literature (natural language

processing) Database issues (including automation) Visualization Mining large complex data sets

Objective Introduction to basic molecular biology to computer science

students by a computer scientist.

A survey of databases: NCBI, SwissProt, PDB, Transfac, … Introduction to computational techniques in analyzing

genomics (and proteomics) data

Communication is important

Textbooks and course website

Required textbooks: Molecular Biology of the Cell (Main text) Bioinformatics, Genomics and Proteomics (Lab) Other material

References: Human Molecular Genetics (2nd Edition available for free) Data Mining : Practical Machine Learning Tools and

Techniques with Java Implementations (The Morgan Kaufmann Series in Data Management Systems) by Ian H. Witten, Eibe Frank (Paperback)

Microarrays for an Integrative Genomics (Computational Molecular Biology) [Paperback] By: Isaac S. Kohane, et al

Molecular Biology Web Book Course website:

http://www.cs.utsa.edu/~kwek/cs6463f05.html

Intended Audience CS graduate students with an interest in

bioinformatics or want to explore bioinformatics. High School Biology.

Not for students who want to find a filler class in between classes.

Every Tuesday noon to 1pm, Human Genome (HuGe) lab meets to discuss current bioinformatics issues. All are welcome even if you are new to bioinformatics (but are taking this course).

Database Search

Course Organization Overview of Molecular Biology (and project discussion)

Databases Introduction to Cell:1. Cells and Genomes2. Cell Chemistry and Biosynthesis3. Proteins

Data preprocessingClassification problemClustering problemMicroarray analysis

Sequence alignmentHidden Markov Model

Basic Genetic Mechanisms4. DNA and Chromosomes6. From DNA to Protein7. Control of gene expression

Diseases:23. Cancer25. PathogensOthers: SNP, NRAi

Gene findingMotif finding

Bioinformatics/Computational Biology Molecular Biology

Project Grade distributions

1 Quiz – 10% 2 tests – 30% Homework and Lab – 10% Project – 50% (+ 10% bonus)

Project Serious in bioinformatics (all HuGe Lab members): Mini (NIH-)

proposal project. Besides preliminary results, a proposal for future work (i.e. independent studies, theses). Possible collaborations with UTHSCSA and others.

Specific Aim(s): What do you want to do? Why is it important? Background: What have been done previously? (What make you

approach interesting?) Where do you get your data? (Preliminary) Result: To elaborate later. Future Work: To elaborate later.

A project: Same as above except do not need to have future work. Office hours (for projects): By appointment (send me an email

24 hours before) Tu, Th 10-3, 5-7, 8:30-10. W 10:30-noon.

Some Important Dates September 13: Quiz 1 (there will be a second chance quiz) September 20: Specific aim of project due. [1 meeting to

discuss with me] October 27: Test 1 October 18: Background of project due. (you must already

started doing experiments) [2 meetings to discuss with me] November 24: Test 2 December 10: Final report of project. [2 meetings to discuss

with me]

IMPORTANT: if you do not meet me the require number of times, I am not accepting your report. Also, each meeting should be at least one week a part.

Your Responsibility

• Read the assigned reading once the material is covered in lecture. Lecture is to make your reading easier.

• Try printing out the slides to take notes.

• Project: Observe the deadline!!!! Come and talk to me.

A. An overview of molecular biology

Read Human Molecular Genetic Ch. 1A.1. BackgroundA.2. MacromoleculesA.3. DNA structureA.4. RNA transcription and Gene ExpressionA.5. RNA processingA.6. Translation, post-translation processing

and protein structureA.7. Project ideas

Two types of cells:1. Prokaryotic (bacteria)2. Eukaryotic (multicellular organisms,Ameba, E. Coli)

A.1 Background: Procaryotic and Eukaryotic Cells

http://www-class.unl.edu/bios201a/spring97/group6/

A.2. Building Blocks: Chemical Composition of Eukaryotic Cell

Water [E. Coli: 70%, Mammalian Cell: 70%] Macro-molecules:

DNA: Deoxyribonucleic Acid [E. Coli: 1%, Mammal: 0.25%] RNA: Ribonucleic Acid [E. Coli: 6%, Mammal: 1.1%] Proteins [E. Coli: 15%, Mammal: 18%]

Inorganic ions: Na+, K+, Mg+, Ca2+, Cl- [E. Coli: 1%, Mammal: 1%] Lipids:

Phospholipids [E. Coli: 2%, Mammal: 3%] Other lipids [E. Coli: -, Mammal: 0.2%]

Polysaccahrides [E. Coli: 1%, Mammal: 0.25%]

Volume: [E. Coli: 2 x 10-12cm, Mammal: 4 x 10-9cm] Relative Volume: [E. Coli: Mammal = 1: 2000]

A.2 Building Blocks: Structure of bases, nucleosides and nucleotides

DNA: ‘polymer of A, G, T, C’RNA: ‘polymer of A, G, U (replace T), C’

Purines:

Pyrimidines:

A.2. Building Blocks: Common bases found in nucleic acids

A.2 Building Blocks: 20 amino acids

Polypeptides: chains of amino acids

Amino groupCarboxyl group

A.2. Building Blocks: Abbreviation of Amino Acids

NameAbbreviation

Linear Structure

Alanine ala A CH3-CH(NH2)-COOH

Arginine arg R HN=C(NH2)-NH-(CH2)3-CH(NH2)-COOH

Asparagine asn N H2N-CO-CH2-CH(NH2)-COOH

Aspartic Acid asp D HOOC-CH2-CH(NH2)-COOH

Cysteine cys C HS-CH2-CH(NH2)-COOH

Glutamic Acid glu E HOOC-(CH2)2-CH(NH2)-COOH

Glutamine gln Q H2N-CO-(CH2)2-CH(NH2)-COOH

Glycine gly G NH2-CH2-COOH

Histidine his H NH-CH=N-CH=C-CH2-CH(NH2)-COOH

Isoleucine ile I CH3-CH2-CH(CH3)-CH(NH2)-COOH

Leucine leu L (CH3)2-CH-CH2-CH(NH2)-COOH

Lysine lys K H2N-(CH2)4-CH(NH2)-COOH

Methionine met M CH3-S-(CH2)2-CH(NH2)-COOH

Phenylalanine

phe F Ph-CH2-CH(NH2)-COOH

Proline pro P NH-(CH2)3-CH-COOH

Serine ser S HO-CH2-CH(NH2)-COOH

Threonine thr T CH3-CH(OH)-CH(NH2)-COOH

Tryptophan trp W Ph-NH-CH=C-CH2-CH(NH2)-COOH

Tyrosine tyr Y HO-Ph-CH2-CH(NH2)-COOH

Valine val V (CH3)2-CH-CH(NH2)-COOH

A.2. Building blocks: Properties of Amino Acids I

http://www.russell.embl-heidelberg.de/aas/aas.html

A.2. Building blocks: Some Terms for describing Properties of Amino Acids

Hydrophobic amino acids are those with side-chains that do not like to reside in an aqueous (i.e. water) environment.

Polar amino acids are those with side-chains that prefer to reside in an aqueous (i.e. water) environment.

Strictly speaking, aliphatic implies that the protein side chain contains only carbon or hydrogen atoms.

A side chain is aromatic when it contains an aromatic ring system.

A.2 Building Blocks: Covalent and Non-covalent Bonds

Covalent bonds: stronger. Nucleic acid and protein polymers are from by covalent binds connecting nucleotides and amino acids (respectively) to form a linear backbone

Non-covalent bonds: weaker and revisible. 4 types:

1. Hydrogen bonds: N – H –O [double-stranded DNA, protein folding, …etc

2. Ionic bonds: Ionic interaction between charged group, sat Na+ and Cl-

3. Van der Waals: Optimum attraction between two atoms.

4. Hydrophobic forces: Water is polar molecules,

A.1. Background A.2. Building Blocks of MacromoleculesA.3. DNA structureA.4. RNA transcription and Gene ExpressionA.5. RNA processingA.6. Translation, post-translation processing

A.3 DNA Structure: The Phosphodiester Bond

A.3 DNA Structure: base pairing (Watson-Crick Rule).

A.3 DNA Structure: DNA is a double-stranded anti-parallel helix

http://www.sumanasinc.com/webcontent/anisamples/molecularbiology/DNA_structure.html

ComplementaryDNA(cDNA)

%GC = 40%? How many % is G? C? A? T?

A.3 DNA Structure: DNA is a double-stranded anti-parallel helix

A.3 DNA Structure: RNA structure

palindrome

A.3 DNA Structure: Viral Genomes

Highly Variable: DNA or RNA Single stranded or double stranded Linear or Circular Segmented and Multipartite

Virus normally replicate in the cytosol. Unusal Retrovirus duplicate itself in the nucleus (using reverse transcriptase)

A.4 DNA Structure: The Central Dogma

Old 1-directional model

A.4 Transcription and Gene Expression:Transcription

exon exon exonintronintronstart stop5’ UTR 3’ UTRpromoterTFBS

5’ 3’

(1st key)

Nuclear membrane

(2nd key, May not be there)

exon exon exonintronintronstart stop5’ UTR 3’ UTR

(complementary nucleotides)

Pre-mRNA poly A

TFBS(almost always there)

(mostly for non-housing gene)

TFBS – Transcription factor binding site

A.4 Transcription and Gene Expression:Gene Regulation

A G T C

U C A G

http://henge.bio.miami.edu/mallery/movies/transcription.mov

http://www-class.unl.edu/biochem/gp2/m_biology/animation/gene/gene_a2.html

A.4 Transcription and Gene Expression:RNA Polymerase

There are three classes of RNA Polymerases: Polymerase I: Localized in the nucleolus. Transcribe

rRNA (ribosome RNA) 28S, 18S 5.8S rRNA. Polymerase II: All protein-coding genes most

smRNAs. Unique in capping and polyadenylation. Polymerase III: tRNA, other rRNAs, snRNAs. [The

promoter can be downstream]

Pusedo-genes (gene fragments): Previously were genes

Only 2% of the human genome encode proteins.

A.4 Transcription and Gene Expression: Trans- and cis-elements

Cis- element DNA sequence Trans-acting Factor

GC Box GGGCGG Spl

TATA Box TATAA TFIID (TFIIA – stabilize it)

CAAT Box CCAAT Many

TRE GTGAGT(A/C)A AP-1 family (many)

CRE (cAMP response element)

GTGACGT(A/C)A(A/G)

CREB/ATF family

Important: If pattern is there, does not necessary mean it is a cis-element.

A.4 Transcription and Gene Expression: Promoters

Start from 1 not 0

A.4 Transcription and Gene Expression: Enhancers and Silencers (Transcription Factors)

Many basepairsaway

A.4 Transcription and Gene Expression: Tissue Specific Genes

House keeping genes: Genes encoding histone protein, ribosome protein. Always on.

Tissue or development-specific (non-housekeeping) genes: Transcriptional inactive chromatin Methylation of Cytosine, replacing a hydrogen (H) with

methyl (CH3) Transcription factors’ expression levels are low.

Microarrays measure the expression levels of genes

A.4 Transcription and Gene Expression:Transcription

exon exon exonintronintronstart stop5’ UTR 3’ UTRpromoterTFBS

5’ 3’

(1st key)

Nuclear membrane

(2nd key, May not be there)

Splicing the introns: http://www.sumanasinc.com/webcontent/anisamples/molecularbiology/mRNAsplicing.html

exon exon exonintronintronstart stop5’ UTR 3’ UTR

(complementary nucleotides)

Pre-mRNA poly A

exon exon exonstart stop5’ UTR 3’ UTRMassager RNA (mRNA) poly A

TFBS(almost always there)

(mostly for non-housing gene)

A.5 RNA Processing: RNA Splicing

donoracceptor

GT-AG spliceosomeAT-AC spliceosome (rare)

A.5 RNA Processing: Consensus Sequences at splice donor, acceptor and branch sites

A.5 RNA Processing: Mechanism of RNA Splicing (GU-AG introns)

Splicesome(5 snRNA)

http://www.nature.com/nrn/journal/v2/n1/animation/nrn0101_043a_swf_MEDIA1.html

A.5 RNA Processing: 5’ End Capping

A.5 RNA Processing: 3’ end polyadenylated.

A.5 RNA Processing: Functions of 5’ End Cap and Poly A tail

Functions of 5’ end cap

1. Prevent mRNA molecules degradation.

2. Facilitate transport to cytoplasm

3. RNA splicing

4. Facilitate translation

Function of 3’ end poly(A) tail

1. Facilitate transport to cytoplasm

2. Stabilize the mRNA in the cytoplasm

3. Facilitate translation

A.5 RNA Processing: Example of the human -globin gene

A.4 RNA Processing: Export out of the nuclear

A.5 RNA Processing: The Codon-anticodon Recognition

http://henge.bio.miami.edu/mallery/movies/translation.mov

(almost always) tRNA

A.6 Translation and Post-Translational Processing : Peptide Bond Formation

A.6 Translation and Post-Translational Processing: The Genetic Codes

N-terminalC-terminal

A.6 Translation and Post-Translational Processing: The Genetic Codes

wobble- mitochondrial

64 possible codons: 1 Start codon AUG. 3 stop codons, 20 amino acids

Signal in mRNAs can lead to alternative interpretation of stop codons:UGA 21st AA selencocysteine, UAG 22nd AA pyrrolysine.

A.6 Translation and Post-Translational Processing: Multiple Post-Translational Cleavages of Polypeptide Precursors

A.6 Translation and Post-Translational Processing: Protein Secondary Structure

A.6 Translation and Post-Translational Processing: Quaternary

Amino acid sequence secondary structure tertiary structure

Amino acid sequence

A.6 Translation and Post-Translational Processing: Quaternary Structure

A.6 Translation and Post-Translational Processing: Disulfide Bridges

A.6 Translation and Post-Translational Processing: Post-translational Modification

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hmg.table.103

A.6 Translation and Post-Translational Processing: Protein Sorting (Localization)

Protein Destination (Typical) Location and form of signal

Endoplasmic reticulum and secretion from cell

N-terminal peptide of 20 or so very hydrophobic AAs.

Mitochondria N-terminal peptide, a-helix. One side hydrophilic and one side hydrophobic

Nucleus Internal sequence of amino acids. Often a string of basic amino acids plus prolines; maybe bipartite.

Lysosome Addition of mannose 6-phosphate residues

1. Signal Peptide

2. Post-translational modification

A.6 Translation and Post-Translational Processing: Cellular Function of Proteins

Diverse cellular functions: Enzymes – ‘cut things into pieces’ Receptors Transport Transcription factor Signaling Hormones Strutural .. etc

A.7 Summary: Central Dogma Simplify

Enzymes, Receptors,... etc

A.7 Summary: Don’t forget about mitochondria!

A.7 Summary: Life is more complex

BiologyOverview.ppt

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