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
1Essential 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
2Lecture 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
3Bioinformatics 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)
4Bioinformatics 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)
5SARS as an example
A novel coronavirus Identified as the cause
of severe respiratory syndrome (SARS )
6SARS as an example
How SARS coronavirus virus enters a cell and
reproduce
7SARS as an example
Another Illustration of SARS Coronavirus Organizat
ion
8SARS Coronavirus Genome
9How 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
10How SARS Coronavirus Is Identified?
11Sequence 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?
12How 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
13How 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 -
14From 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
15How 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
16Modeling 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.
17Modeling the SARS-CoV Protein Structure
18Modeling the protein motions
Movie Show Drug Binding Induced Conformation
Change in Protein
19Modeling the protein motions
Movie Show Protein transient opening for ligand
or drug binding and dissociation
20Drug Design by Computer Ligand-Protein Docking
- Computer search for stable drug-protein complex
21.
22.
23.
24.
25Anti-SARS Drug Design
26Design 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)
27General 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)
28Construction 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.
29Bioinformatics software
- Its role in research
- Hypothesis-driven research cycle in biology (From
Kitano H. Systems biology a brief overview.
Science 2002, 2951662-4)
30Bioinformatics 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).
31Bioinformatics 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.
32Bioinformatics 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