Essential Bioinformatics and Biocomputing (LSM2104: Section I) Biological Databases and Bioinformatics Software Prof. Chen Yu Zong Tel: 6874-6877 Email: csccyz@nus.edu.sg http://xin.cz3.nus.edu.sg Room 07-24, level 7, SOC1, NUS January 2003 - PowerPoint PPT Presentation

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Essential Bioinformatics and Biocomputing (LSM2104: Section I) Biological Databases and Bioinformatics Software Prof. Chen Yu Zong Tel: 6874-6877 Email: csccyz@nus.edu.sg http://xin.cz3.nus.edu.sg Room 07-24, level 7, SOC1, NUS January 2003

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Examples of bioinformatics software usage: After the discovery of a new gene or protein related to a ... Using structure of other coronavirus as a template ... – PowerPoint PPT presentation

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Title: Essential Bioinformatics and Biocomputing (LSM2104: Section I) Biological Databases and Bioinformatics Software Prof. Chen Yu Zong Tel: 6874-6877 Email: csccyz@nus.edu.sg http://xin.cz3.nus.edu.sg Room 07-24, level 7, SOC1, NUS January 2003


1
Essential Bioinformatics and Biocomputing
(LSM2104 Section I) Biological Databases
andBioinformatics SoftwareProf. Chen Yu
ZongTel 6874-6877Email csccyz_at_nus.edu.sghttp
//xin.cz3.nus.edu.sgRoom 07-24, level 7, SOC1,
NUSJanuary 2003
2
Lecture 4 Bioinformatics software
  • Outline
  • Examples of Bioinformatics software usage
  • Questions and strategies for dealing with
    biomedical problems
  • SARS as an example
  • SARS genome
  • How to figure out the function of SARS genes?
  • Use of info of SARS genes in drug design
  • Bioinformatics software and research

3
Bioinformatics software
  • Examples of bioinformatics software usage
  • After the discovery of a new gene or protein
    related to a
  • disease, these questions are usually asked
  • What is its function and structure?
  • Is it similar in sequence to a known gene or
    protein? (sequence similarity search)
  • Does it contain sequence pattern similar to that
    of a group of known genes or proteins? (motif
    identification)
  • Is this protein similar to proteins with known
    3D structure? If so, derive a 3D model (protein
    homology modeling)

4
Bioinformatics software
  • After the discovery of a new gene or protein
    related to a
  • disease, these questions are usually asked
  • Has any research been done on the disease or
    similar genes/proteins? (literature search, data
    mining)
  • How to design a new drug to control it?
  • If 3D structure is known or can be derived,
    structure-based drug design can be conducted
    (molecular modeling, docking)
  • If 3D structure not known, are there any
    molecules known to interact with this protein
    (literature search, data mining)? If yes, predict
    the likely drug candidates based on statistic
    analysis of these molecules (QSAR, machine
    learning)

5
SARS as an example
A novel coronavirus Identified as the cause
of severe respiratory syndrome (SARS )
6
SARS as an example
How SARS coronavirus virus enters a cell and
reproduce
7
SARS as an example
Another Illustration of SARS Coronavirus Organizat
ion
8
SARS Coronavirus Genome
9
How SARS Coronavirus Is Identified?
  • SARS pathogen related to an existing virus or
    bacterium?
  • Key SARS proteins must be similar to the proteins
    of that virus or bacterium so that they have
    similar organization, metabolic machinery etc.
  • Protein similarity Sequence similarity (based
    on the principles of evolution and the
    sequence-structure-function relationship)
  • What has been found
  • Key SARS proteins are similar to those of
    coronavirus
  • Some SARS proteins are not similar to any
    existing proteins
  • Conclustion SARS pathogen is a novel coronavirus

10
How SARS Coronavirus Is Identified?
11
Sequence Comparison as a Mathematical Problem
  • Example
  • Sequence a  ATTCTTGC
  • Sequence b ATCCTATTCTAGC  
  •          Best Alignment             ATTCTTGC
                                     ATCCTATTCTAGC
                                           /\
                     gap    
       Bad Alignment AT     TCTT       GC
                                     ATCCTATTCTAGC
                                                      
               /\            
    /\                                      gap     
         gap
  • Construction of many alignments gt which is the
    best?  

12
How to rate an alignment?
  • Match 8 (w(x, y) 8, if x y)
  • Mismatch -5 (w(x, y) -5, if x ? y)
  • Each gap symbol -3 (w(-,x)w(x,-)-3)

C - - - T T A A C TC G G A T C A - - T
8 -3 -3 -3 8 -5 8 -3 -3
8 12
Alignment score
13
How to rate an alignment?
  • Alignment example
  • Sequence a AGTACAT - A
  • Sequence b A - CACACTA
  • Pair  Status Scoring function
  • (A, A) Match w8
  • (G, -) Gap w-3
  • (T, C) Mismatch w-5
  • (A, A) Match w8
  • (C, C) Match w8
  • (A, A) Match w8
  • (T, C) Mismatch w-5
  • (- , T) gap w-3
  • (A, A) Match w8 Total
    score  S 24


14
From Math Algorithm to Computer Program
  • Example
  • A program that calls each computer in your
    lab, and expect them to respond by sending a
    message
  • hello from processor n


15
How to design an anti-SARS drug?
  • Mechanism of
  • Drug Action
  • A drug interferes with the function of a
    disease protein by binding to it.
  • This interference stops the disease process
  • Drug Design
  • Structure of disease protein is very useful

16
Modeling the SARS-CoV Protein Structure
Strategy Using structure of other coronavirus
as a template Assuming backbone structure is
fixed, gradually mutate the sequence from that of
the other coronavirus to that of SARS-CoV.
17
Modeling the SARS-CoV Protein Structure
18
Modeling the protein motions

Movie Show Drug Binding Induced Conformation
Change in Protein
19
Modeling the protein motions

Movie Show Protein transient opening for ligand
or drug binding and dissociation
20
Drug Design by Computer Ligand-Protein Docking
  • Computer search for stable drug-protein complex

21
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22
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23
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24
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25
Anti-SARS Drug Design
26
Design of anti-SARS drug without knowledge of
protein structure
  • Log(Biological activity of drug candidate) gt
  • Size of a side chain of drug candidate
  • (gt Size and shape of protein cavity)

27
General Principles
  • Log(Biological activity)
  • f(structural, physico-chemical parameters)
  • Example
  • Log(Biological activity) gt
  • Combination of hydrophobic group and
  • charged groups
  • (gt Chemical complementarity to protein cavity)

28
Construction of Drug Framework
  • Superimposing common molecular
  • interaction field contour resulted
  • in the identification of
  • the consensus framework
  • The Concensus Framework
  • purple hydrophobic area
  • green electron-deficient aromatic system
  • red electronegative heteroatoms
  • pink protonated nitrogen
  • blue large planar ring system.

29
Bioinformatics software
  • Its role in research
  • Hypothesis-driven research cycle in biology (From
    Kitano H. Systems biology a brief overview.
    Science 2002, 2951662-4)

30
Bioinformatics software
  • Cyclical refinement of predictive computer models
    used to define further biological experiments,
    including the optimization step. (From Brusic et
    al. 2001, Efficient discovery of immune response
    targets by cyclical refinement of QSAR models of
    peptide binding. J. Mol. Graph. Model. 19405-11,
    467).

31
Bioinformatics software
  • By combining computational methods with
    experimental biology, major discoveries can be
    made faster and more efficiently.
  • Today, every large molecular or systems biology
    project has a bioinformatics component.
  • Use of biological software allows biologists to
    extend their set of skills for more efficient and
    more effective analysis of their data, and for
    planning of experiments.

32
Bioinformatics software Summary of Todays
lecture
  • What is and Why bioinformatics software?
  • SARS research as an example
  • SARS genome
  • Figure out the function of SARS proteins
  • Drug design
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