Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

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Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS

Transcript of Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Page 1: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Introduction toComputational Biology

BS123A/BME195/MB223

UC-Irvine

Ray Luo, MBB, BS

Page 2: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

What to expect?

• This is an introduction to computational representations and algorithms for analysis of sequence, structure and function in molecular biology. It aims to give an understanding of the biological problems that arise and how algorithms are developed to address them.

Page 3: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Goals of this course

• Learn how to present molecular data using computer graphics

• Understand computational challenges in molecular biology

• Understand basic algorithms that establish context for rest of field

• Identify opportunities in this field, and perhaps formulate projects to explore further

Page 4: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

How to reach these goals?

• Give you a feeling for main issues in computational molecular biology: sequence, structure, and function

• Give you exposure to classic computational problems as manifested in biology.

• Give you exposure to classic biological problems represented computationally.

Page 5: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Things that won’t be emphasized

• Won’t give you any balanced understanding of the experimental approaches used in molecular biology.

• Won’t force you to make a novel contribution to computational biology.

• Won’t ask you to write a computer program for any project, though you’re require to describe how a program/algorithm work in English.

Page 6: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Prerequisite

• Freshman calculus, phys, and chem completed or being taken concurrently.

• Willing to think quantitatively in biology.

• Willing to use computer in learning/working.

Page 7: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Course website

• http://rayl0.bio.uci.edu/teaching

• Lecture notes will be posted before the lectures if possible.

• Handouts will be passed around for additional information.

Page 8: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Contacts

• Office hours by appointment

[email protected]

• 3206 Natural Sciences I

Page 9: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Lecture info

• Meeting place: NSI 2144

• Meeting times: Tue/Thur 9:00-10:30am

Page 10: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Grading

o 50% based on weekly homework/projecto 25% by in-class finalo 25% by take-home final

Page 11: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Grading: How to get an A?

• It is crucial to turn in weekly homework and projects to get a passing grade.

• The finals are 90% based on homework and projects so make sure you know each assigned problem well for the finals. You have to do the in-class final very fast.

Page 12: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Uses of Computation in Biology

• Ecology

• Physiology

• Cell Biology

• Molecular Biology

Page 13: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Careers in Computational Molecular Biology

• Pharmaceutical/Biotechnology Industry

• Universities and Colleges

Page 14: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Life in Industry

• Identification of potential drug targets, mostly enzymes, with molecular biologist and biochemists

• Discovery of lead compounds, with medicinal chemists, aka organic chemists

• Optimization of lead compounds, with medical chemists

• Prediction of drug-like properties, ADME-T (absorption, distribution, metabolism, excretion, toxicity )

Page 15: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Why the things you learn here are important?

Computer aided drug design

Page 16: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

What is a drug?

• Defined composition with a pharmacological effect

• Regulated by the Food and Drug Administration (FDA)

• What is the process of Drug Discovery and Development?

Page 17: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Drugs and the Discovery Process

• Small Organic Molecules– Natural products

• fermentation broths • plant extracts • animal fluids (e.g., snake venoms)

– Synthetic Medicinal Chemicals• Project medicinal chemistry derived• Combinatorial chemistry derived

• Biological Molecules– Natural products (isolation)– Recombinant products

Page 18: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Discovery vs. Development

• Discovery includes: Concept, mechanism, assay, screening, hit identification, lead demonstration, lead optimization

• Discovery also includes In Vivo proof of concept in animals and demonstration of a therapeutic effect

• Development begins when the decision is made to put a molecule into phase I clinical trials

Page 19: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Discovery and Development

• The time from conception to approval of a new drug is typically 10-15 years

• The vast majority of molecules fail along the way• The estimated cost to bring to market a

successful drug is now $800 million!! (Dimasi, 2000)

• However, the annual profit of a drug can be $ 1 billion per year

• Pharmaceutical industry has been one of the best performing sections in economy

Page 20: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Drug Discovery Disciplines

• Medicine• Physiology/pathology• Pharmacology• Molecular/cellular biology• Automation/robotics• Medicinal, analytical,and combinatorial

chemistry• Structural and computational chemistries• Computational biology

Page 21: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Drug Discovery Program Rationales

• Unmet Medical Need

• Me Too! - Market - ($$$s)

• Drugs in search of indications– Side-effects often lead to new indications

• Indications in search of drugs– Mechanism based, hypothesis driven,

reductionism

Page 22: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Issues in Drug Discovery

• Hits and Leads - Is it a “Druggable” target?

• Resistance

• Delivery - oral and otherwise

• Metabolism

• Solubility, toxicity

• Patentability

• … …

Page 23: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

A Little History of Computer Aided Drug Design

• 1960’s - Review target-drug interactions• 1980’s- Automation - high throughput target/drug selection• 1980’s- Databases (information technology) - combinatorial libraries• 1980’s- Fast computers - docking• 1990’s- Faster computers - genome assembly - genomic based target selection• 2000’s- Fast information handling - pharmacogenomics

Page 24: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

From the Computer Perspective

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Comparing Growth Rates

0

5

10

15

20

25

30

35

40

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Inc

rea

se

fa

cto

rProcessor performance growth

Memory bus speed growth

Pixel fill rate growth

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From the Target Perspective

Page 27: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

(a) myoglobin (b) hemoglobin (c) lysozyme (d) transfer RNA(e) antibodies (f) viruses (g) actin (h) the nucleosome (i) myosin (j) ribosome

Status - Numbers and Complexity

Courtesy of David Goodsell, TSRI

Page 28: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

From the Drug Perspective

Page 29: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Combinatorial Libraries

Blaney and Martin - Curr. Op. In Chem. Biol. (1997) 1:54-59

• Thousands of variations to a fixed template• Good libraries span large areas of chemical and conformational space - molecular diversity• Diversity in - steric, electrostatic, hydrophobic interactions...• Desire to be as broad as “Merck” compounds from random screening• Computer aided library design is in its infancy

Page 30: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Computer-Assisted Drug Design

• Computer driven drug discovery• Data driven drug discovery

Page 31: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

An overview of biomolecules

• Living organisms are more ordered than their surroundings.

• So the first task is to maintain a separation between inside and outside.

• The second task is to spend energy to keep things in order.

• The functions of life are to facilitate the acquisition and expenditure of energy.

Page 32: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Cell

• Cells are the smallest compartments that are ordered and separated from the surroundings.

• Note that ordered compartments were difficult to get started de novo, and so have found ways to pass on the apparatus necessary to perpetuate themselves.

Page 33: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Tasks of a living cell

• Gather energy from surroundings.• Use energy to maintain inside/outside

distinction.• Use extra energy to reproduce.• Develop strategies for being efficient at

their tasks: developing ways to move around; developing signaling capabilities; developing ways for energy capture; developing ways of reproduction.

Page 34: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Molecular means to realizethese tasks

• Ability to separate inside from outside with lipids

• Ability to build three-dimensional molecules that assist their functions, proteins, RNA

• Ability to store information for these tasks, part of reproduction also, DNA

Page 35: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

A simple model of a cell

proteins Lipid membrane DNA

Page 36: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Lipids

• Made of hydrophilic (water loving) molecular fragment connected to hydrophobic fragment.

• Spontaneously form sheets (lipid bilayers, membranes) in which all the hydrophilic ends align on the outside, and hydrophobic ends align on the inside.

• Creates a very stable separation, not easy to pass through except for water and a few other small atoms/molecules.

Page 37: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Lipids

Page 38: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Lipid bilayers: Structure

Page 39: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Lipid bilayers: Structure

Page 40: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Lipid bilayers: Functions

Page 41: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Lipid bilayers

Page 42: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

A simple model of a cell

proteins Lipid membrane DNA

Page 43: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Proteins: A chain of linked subunits

• These subunits are amino acids (also called protein residues for historical reasons).

• There are 20 different amino acids with different physical and chemical properties.

• The interaction of these properties allows a chain of the amino acids (upto 1000’s long) to fold into a unique, reproducible 3D shape.

Page 45: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Amino acid structures

Fig. 5.3

Page 46: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Fig. 5.3

Page 47: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Amino acid properties

• Polar amino acids: THR, SER, ASN, GLN, TYR, HIS, TRP, CYS

• Charged amino acids: ASP, GLU, LYS, ARG, HIS, CYS

• Hydrophobic amino acids: VAL, LEU, ILE, PHE, ALA, PRO, GLY, MET, TYR, TRP

Page 48: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Representations of proteins

• 1-d sequence:

Alanine-Tyrosine-Valine=

ALA-TYR-VAL=

A-Y-V

Page 49: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Representations of proteins: 2-dTHH HHHHHTLLLH HHHHHGGGLS STTEEEEEEE

Page 50: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Representations of proteins: 3-d

Page 51: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Protein features

• Protein can be stabilized by salt bridges

• Protein can be folded to a unique structure due to the existence of disulfide bonds

• Protein may function as an enzyme whose active sites are crucial for its function

Page 52: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

A simple model of a cell

proteins Lipid membrane DNA

Page 53: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

DNA structures

DNA packs in the nucleus toform chromosome

Page 54: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

DNA structure

Page 55: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

DNA is a sequence too

• It has a common back bone, and side chains, though only 4 kinds.

• A sequence of these subunits is also specified as a string: ACTTAGGACATTTTAG, which is a simplified representation of a chemical structure.

Page 56: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

DNA is a sequence too

• DNA uses an alphabet of 4 letters (ATCG), i.e. bases.

• Long sequences of these 4 letters are linked together to create genes and control information.

Page 57: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Information in DNA

• DNA encodes proteins: each amino acid can be specified by 3 bases. Ribosome reads a DNA sequence and creates the corresponding protein chain.

• GENETIC CODE: 64 mappings of 3 bases to 1 amino acid.

Page 58: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Genetic code

Page 59: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

The gene for myoglobin• ctgcagataa ctaactaaag gagaacaaca acaatggttc tgtctgaagg• tgaatggcag ctggttctgc atgtttgggc taaagttgaa gctgacgtcg• ctggtcatgg tcaggacatc ttgattcgac tgttcaaatc tcatccggaa• actctggaaa aattcgatcg tttcaaacat ctgaaaactg aagctgaaat• gaaagcttct gaagatctga aaaaacatgg tgttaccgtg ttaactgccc• taggtgctat ccttaagaaa aaagggcatc atgaagctga gctcaaaccg• cttgcgcaat cgcatgctac taaacataag atcccgatca aatacctgga• attcatctct gaagcgatca tccatgttct gcattctaga catccaggta• acttcggtgc tgacgctcag ggtgctatga acaaagctct cgagctgttc• cgtaaagata tcgctgctaa ctgggttacc agggttaatg aggtacc

BASE COUNT 155 a 108 c 115 g 129 t

MVLSEGEWQLVLHVWAKVEADVAGHGQDILIRLFKSHPETLEKFDRFKHLKTEAEMKASEDLKKHGVTVLTALGAILKKKGHHEAELKPLAQSHATKHKIPIKYLEFISEAIIHVLHSRHPGNFGADAQGAMNKALELFRKDIAAKYKELGYQG

Page 60: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.
Page 61: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Genes and control

• The set of all genes required for an organism is the organism’s GENOME.

• Human genome has 3,000,000,000 bases divided into 23 linear segments (chromosomes).

• A gene has on average 1340 DNA bases, thus specifying a protein of about 447 amino acids.

• Humans have about 35,000 genes = 40,000,000 DNA bases = 3% of total DNA in genome.

• Humans have another 2,960,000,000 bases for control information. (e.g. when, where, how long, etc...)

Page 62: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Genotype and phenotype

• Genotype—the genetic sequences associated with an individual organism.

• Phenotype—the observable non-sequence features of an individual organism (e.g. color, shape, activity of an enzyme)

Page 63: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

How do we proceed?

In order to obtain insight into the ways in which genes and gene products function:

• Analyze DNA and protein sequences to search clues for structure, function and control – sequence analysis

• Analyze structures to search clues for sequences, function and control – structural analysis

• Understand how sequences and structures leads to functions – functional analysis

Page 64: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

But what are functions of genes?

• Signal transduction: sensing a physical signal and turning into a chemical signal

• Structural support: creating the shape and of a cell or set of cells

• Enzymatic catalysis: accelerating chemical reactions otherwise too slow to be useful for living things

• Transport: getting things in and out of a compartment.

Page 65: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

But what are functions of genes?

• Movement: contracting in order to pull things together or push things apart

• Transcription control: deciding when other genes should be turned on/off

• Trafficking: affecting where different elements end up inside a cell.

Page 66: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Evolution is the key

• Common descent of organisms implies that they will share many basic approaches

• Development of new phenotypes in response to environmental pressure can lead to specialized approaches

• More recent divergence implies more shared approaches between species

• The important thing is which is shared and which is not unshared. This is also important for drug discovery in biomedicine.

Page 67: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Seeing is believing:Computer Graphics

Page 68: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

Je-2147/HIV Protease Complex

Page 69: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

HIV Integrase

Page 70: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

The Small Ribosomal Subunit

Page 71: Introduction to Computational Biology BS123A/BME195/MB223 UC-Irvine Ray Luo, MBB, BS.

The Large Ribosomal Subunit