1 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Doç. Dr. Nizamettin AYDIN Introduction to Bioinformatics

2 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Recommended Texts

3 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Recommended Texts - 2

4 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Recommended Texts - 3

5 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Recommended Texts - 4 Bioinformatics for Dummies Jean Claverie, Cedric Notredame Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins Andreas D. Baxevanis, B. F. Ouellette, Ouellette B. F. Francis. Instant Notes in Bioinformatics D. R. Westhead, Richard M. Twyman, J. H. Parish Bioinformatics: Sequence and Genome Analysis, Vol. 5 David W. Mount, David Mount Developing Bioinformatics Computer Skills Cynthia Gibas, Per Jambeck, Lorrie LeJeune (Editor) Discovering Genomics, Proteomics, and Bioinformatics A. Malcolm Campbell, Laurie J. Heyer

6 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Recommended Texts - 5 Structural Bioinformatics Philip E. Bourne (Editor), Helge Weissig Beginning Perl for Bioinformatics James Tisdall Mastering Perl for Bioinformatics James D. Tisdall

7 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” What is Bioinformatics?...

8 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN”...What is Bioinformatics?... Computational Biology Bioinformatics Genomics Proteomics Functional genomics Structural bioinformatics

9 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN”...What is Bioinformatics? Bioinformatics: collection and storage of biological information Computational biology: development of algorithms and statistical models to analyze biological data Bioinformatics/Computational Biology will be interchanged

10 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Why is Bioinformatics Important? Applications areas include –Medicine –Pharmaceutical drug design –Toxicology –Molecular evolution –Biosensors –Biomaterials –Biological computing models –DNA computing

11 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Why should I care? SmartMoney ranks Bioinformatics as #1 among next HotJobs Business Week 50 Masters of Innovation Jobs available, exciting research potential Important information waiting to be decoded!

12 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Why is bioinformatics hot? Supply/demand: few people adequately trained in both biology and computer science Genome sequencing, microarrays, etc lead to large amounts of data to be analyzed Leads to important discoveries Saves time and money

13 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” The Role of Computational Biology Source: GenBank 3D Structures Growth: Source: holdings.html GenBank BASEPAIR GROWTH

14 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Fighting Human Disease Genetic / Inherited –Diabetes Viral –Flu, common cold Bacterial –Meningitis, Strep throat

15 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Drug Development Life Cycle Years Discovery (2 to 10 Years) Preclinical Testing (Lab and Animal Testing) Phase I (20-30 Healthy Volunteers used to check for safety and dosage) Phase II ( Patient Volunteers used to check for efficacy and side effects) Phase III ( Patient Volunteers used to monitor reactions to long-term drug use) FDA Review & Approval Post-Marketing Testing $ Million! 7 – 15 Years!

16 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Drug lead screening 5,000 to 10,000 compounds screened 250 Lead Candidates in Preclinical Testing 5 Drug Candidates enter Clinical Testing; 80% Pass Phase I One drug approved by the FDA 30%Pass Phase II 80% Pass Phase III

17 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” What skills are needed? Well-grounded in one of the following areas: –Computer science –Molecular biology –Statistics Working knowledge and appreciation in the others!

18 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Where Can I Learn More? ISCB: NBCI: Journals Conferences

19 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Overview of Molecular Biology Cells Chromosomes DNA RNA Amino Acids Proteins Genome/Transcriptome/Proteome

20 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Cells Complex system enclosed in a membrane Organisms are unicellular (bacteria, baker’s yeast) or multicellular Humans: – 60 trillion cells –320 cell types Example Animal Cell biology_intro.htm

21 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Organisms Classified into two types: Eukaryotes: contain a membrane-bound nucleus and organelles (plants, animals, fungi,…) Prokaryotes: lack a true membrane-bound nucleus and organelles (single-celled, includes bacteria) Not all single celled organisms are prokaryotes!

22 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Chromosomes In eukaryotes, nucleus contains one or several double stranded DNA molecules organized as chromosomes Humans: –22 Pairs of autosomes –1 pair sex chromosomes Human Karyotype Session8/Session8.html

23 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Chromosomes Image source:

24 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” DNA is the blueprint for life DNA: Deoxyribonucleic Acid Every cell in your body has 23 chromosomes in the nucleus The genes in these chromosomes determine all of your physical attributes. Single stranded molecule (oligomer, polynucleotide) chain of nucleotides 4 different nucleotides: –Adenosine (A) –Cytosine (C) –Guanine (G) –Thymine (T)

25 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Mapping the Genome The human genome project has provided us with a draft of the entire human genome. Four bases: A, T, C, G 3.12 billion base- pairs 99% of these are the same Polymorphisms = where they differ

26 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Nucleotide Bases Purines (A and G) Pyrimidines (C and T) Difference is in base structure Image Source: biology_intro.htm

27 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” DNA Can be thought of as an alphabet with 4 characters 4 letter alphabet with sufficiently long words contains information to create complex organisms Not unlike a computer with a small alphabet

28 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” DNA polynucleotides(oligomers) Different nucleotides are strung together to form polynucleotides Ends of the polynucleotide are different A directionality is present Convention is to label the coding strand from 5 ’ to 3 ’

29 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Single Strand Polynucleotide Example polynucleotide: 5’ G  T  A  A  A  G  T  C  C  C  G  T  T  A  G  C 3’

30 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Double Stranded DNA DNA can be single-stranded or double-stranded Double stranded DNA: second strand is the “ reverse complement ” strand Reverse complement runs in opposite direction and bases are complementary Complementary bases: –A, T –C, G

31 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Double Stranded Sequence Example double stranded polynucleotide: 5’ G  T  A  A  A  G  T  C  C  C  G  T  T  A  G  C 3’ | | | | | | | | 3’ C  A  T  T  T  C  A  G  G  G  C  A  A  T  C  G 5’

32 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Double Stranded DNA

33 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Double Helix Two complementary DNA strands form a stable DNA double helix This spring marks the 50 th anniversary of its discovery Image source; biology_intro.htm

34 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN”

35 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” How does the code work? Template for construction of proteins

36 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Proteins: Molecular machinery Proteins in your muscles allows you to move: myosin and actin

37 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Proteins: Molecular machinery Enzymes (digestion, catalysis) Structure (collagen)

38 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Proteins: Molecular machinery Signaling (hormones, kinases) Transport (energy, oxygen) Image source: Crane digital,

39 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” 1.Exposure & infection 2.HIV enters your cell 3.Your own cell reads the HIV “code” and creates the HIV proteins. 4.New viral proteins prepare HIV for infection of other cells. © George Eade, Eade Creative Services, Inc. Example Case: HIV Protease

40 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” HIV Protease & Inhibition

41 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Many drugs bind to protein active sites. This HIV protease can no longer prepare HIV proteins for infection, because an inhibitor is already bound in its active site. HIV Protease + Peptidyl inhibitor (1A8G.PDB) HIV Protease as a drug target

42 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Target Identification –What protein can we attack to stop the disease from progressing? Lead discovery & optimization –What sort of molecule will bind to this protein? Toxicology –Does it kill the patient? –Does it have side effects? –Does it get to the problem spots? Drug Discovery

43 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Put some of the infectious agent into thousands of tiny wells Add a known drug lead compound into each well. –Try nearly every drug lead known. See which ones kill the agent… –Too small to see, so we have to use chemical tests called assays Drug discovery: past & present

44 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Once we have a target, how do we find some compounds that might bind to it? The old way: exhaustive screening The new way: computational screening! Finding drug leads

45 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Complementarity –Shape –Chemical –Electrostatic ? ? Drug Lead Screening & Docking

46 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Genomics –Gene finding –Annotation Sequence alignment and database search –Functional genomics Microarray expression, “gene chips” Proteomics –Structure prediction Comparative modeling –Function prediction Structural bioinformatics –Molecular docking, screening, etc. Problems in Bioinformatcs

47 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” RNA Ribonucleic Acid Similar to DNA Thymine (T) is replaced by uracil (U) RNA can be: –Single stranded –Double stranded –Hybridized with DNA

48 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” RNA RNA is generally single stranded Forms secondary or tertiary structures RNA folding will be discussed later Important in a variety of ways, including protein synthesis

49 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” RNA secondary structure E. coli Rnase P RNA secondary structure

50 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” mRNA Messenger RNA Linear molecule encoding genetic information copied from DNA molecules Transcription: process in which DNA is copied into an RNA molecule

51 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” mRNA processing Eukaryotic genes can be pieced together –Exons: coding regions –Introns: non-coding regions mRNA processing removes introns, splices exons together Processed mRNA can be translated into a protein sequence

52 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” mRNA Processing Image source:

53 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” tRNA Transfer RNA Well-defined three-dimensional structure Critical for creation of proteins

54 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” tRNA structure

55 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” tRNA Amino acid attached to each tRNA Determined by 3 base anticodon sequence (complementary to mRNA) Translation: process in which the nucleotide sequence of the processed mRNA is used in order to join amino acids together into a protein with the help of ribosomes and tRNA

56 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Genetic Code 4 possible bases (A, C, G, U) 3 bases in the codon 4 * 4 * 4 = 64 possible codon sequences Start codon: AUG Stop codons: UAA, UAG, UGA 61 codons to code for amino acids (AUG as well) 20 amino acids – redundancy in genetic code

57 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” 20 Amino Acids Glycine (G, GLY) Alanine (A, ALA) Valine (V, VAL) Leucine (L, LEU) Isoleucine (I, ILE) Phenylalanine (F, PHE) Proline (P, PRO) Serine (S, SER) Threonine (T, THR) Cysteine (C, CYS) Methionine (M, MET) Tryptophan (W, TRP) Tyrosine (T, TYR) Asparagine (N, ASN) Glutamine (Q, GLN) Aspartic acid (D, ASP) Glutamic Acid (E, GLU) Lysine (K, LYS) Arginine (R, ARG) Histidine (H, HIS) START: AUG STOP: UAA, UAG, UGA

58 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Amino Acids building blocks for proteins (20 different) vary by side chain groups Hydrophilic amino acids are water soluable Hydrophobic are not Linked via a single chemical bond (peptide bond) Peptide: Short linear chain of amino acids (< 30) polypeptide: long chain of amino acids (which can be upwards of 4000 residues long).

59 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Proteins Polypeptides having a three dimensional structure. Primary –sequence of amino acids constituting the polypeptide chain Secondary – local organization into secondary structures such as  helices and  sheets Tertiary – three dimensional arrangements of the amino acids as they react to one another due to the polarity and resulting interactions between their side chains Quaternary – number and relative positions of the protein subunits

60 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Protein Structure

61 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Central Dogma DNA  RNA  PROTEIN

62 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Central Dogma

63 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” What is a Gene? the physical and functional unit of heredity that carries information from one generation to the next DNA sequence necessary for the synthesis of a functional protein or RNA molecule

64 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Genome chromosomal DNA of an organism number of chromosomes and genome size varies quite significantly from one organism to another Genome size and number of genes does not necessarily determine organism complexity

65 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Genome Comparison ORGANISMCHROMOSOMESGENOME SIZEGENES Homo sapiens Homo sapiens (Humans) 233,200,000,000~ 30,000 Mus musculus (Mouse) 202,600,000,000~30,000 Drosophila melanogaster Drosophila melanogaster (Fruit Fly) 4180,000,000~18,000 Saccharomyces cerevisiae (Yeast) 1614,000,000~6,000 Zea mays (Corn)102,400,000,000???

66 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Transcriptome complete collection of all possible mRNAs (including splice variants) of an organism. regions of an organism’s genome that get transcribed into messenger RNA. transcriptome can be extended to include all transcribed elements, including non-coding RNAs used for structural and regulatory purposes.

67 “INTRODUCTION TO BIOINFORMATICS” “SPRING 2005” “Dr. N AYDIN” Proteome the complete collection of proteins that can be produced by an organism. can be studied either as static (sum of all proteins possible) or dynamic (all proteins found at a specific time point) entity