Computational Biology

May 8, 2004MUPGRET Workshop

Overview Math Statistics Computer Models Bioinformatics

Math and Science Mathematics are an integral part of

science. Used everyday by bench scientists

to perform experiments, interpret data, and make predictions.

Math Examples Making solutions Plotting graphs Calculating area

Area calculations NIH Image Software http://rsb.info.nih.gov/nih-image/D

efault.html Allows you to measure length,

width, area, density on objects in a picture.

Free

Statistics and Science Necessity for analyzing datasets. Experiment must be well designed

to be meaningful. Ex. replications and controls Should know how you’ll analyze data

before you start the experiment. Means, standard deviations, and

linear regression are often used.

Probability Tests the likelihood that something

will or will not occur. Used extensively in everyday life.

Las Vegas type gaming Lotto Insurance amortization Decisions regarding medical

treatment

Everyday examples Rolling the dice

1 in 6 chance that you will roll a one with a single die.

(1/6)2 = 1/36 chance you will roll snake eyes.

Playing cards 4 in 52 chance (1/13) of drawing an

ace at random from a deck. What’s the chance of a full house?

Biology examples Punnett square Nucleotide frequencies along a gene

are used to examine evolutionary forces.

Mutation rates Testing limits and sample sizes for

transgenics. DNA forensics

Computers Data quality Data storage Data analysis Data validation Data manipulation

Barcode systems

The “ics” Genomics Proteomics Metabolomics Bioinformatics

Bioinformatics Revolutionized our ability to do biology

in much the same way as PCR and robotics changed the bench science.

“the computational branch of molecular biology” (Bioinformatics for Dummies).

a merger of computer science and biology (Introduction to Bioinformatics)

Before bioinformatics In vivo experiments

In the living organism In vitro experiments

In a test tube

Manhattan Project Space Program Human Genome Project

Progress towards the HGP 1953-DNA structure 1975-Maxim and Gilbert DNA

sequencing 1977- First genome sequenced

(x174) 1981-Human mitochondrial genome

sequenced 1984-Epstein Barr virus sequenced

Progress towards the HGP 1990- Human genome project

launched 1992-TIGR formed 1996-High resolution map of the

human genome 1998-C. elegans genome sequenced 1999-Drosophila genome sequenced 2000-Draft sequence of human

genome completed.

Bioinformatics Integration of computer science

and biology Applied field Inference Connection Prediction

The basics DNA sequence protein sequence protein sequence protein

structure protein structure protein

function

Bioinformatics Computer simulation Data management and retrieval Pattern recognition Artificial intelligence

Data management/retrieval Database design and

implementation Data entry tools Distributed computing Querying tools

www.mgdb.org

Pattern Recognition DNA sequence analysis

www.ncbi.nlm.nih Geneology Disease diagnosis

Artificial intelligence Software learns from the data it is

given and modifies its programs to be more efficient or to be more accurate. Proteomics software Disease diagnostic imaging

Computer Science Algorithm-program that specifies

how to solve a problem Data structure and information

retrieval Software engineering

The human side Curation Annotation Quality control design

Examples of utility Determining phylogenetic

relationships Sequence similarities Protein structure prediction Disease diagnosis Pharmacogenomics

Detailed structure information Requires crystallization of the

protein. Large amount of protein required. Often time consuming. Limiting step to high throughput.

Followed by X-ray crystallography or NMR. Determines position of each atom in

the molecule.

A Rational Approach Christendat et al. 2000. Nat.

Struct. Biol. 7:903-908. Determine structure of all proteins

in Methanobacterium thermoautotrophicum. 1871 ORFs

The dilemma Cell membrane is “semipermeable”

and comprised of phospholipids. Only hydrophobic molecules can

pass through cell membranes. Conversely, no charged (polar)

molecules. Water can pass through membranes.

Water is a polar molecule.

Aquaporin-1 First water channel protein cloned. Water travels through aquaporin

rather than phospholipid bilayer. Water can pass through but

protons can’t. Membrane potential Hydrogen gradients

Aquaporin But protons can move along a

column of water so how does aquaporin prevent this?

Monomer has 269 aa with 6 membrane spanning domains.

Heterotetramer is the functional molecule.

Aquaporin Protein has a hourglass shape. The narrowest place is 3.0 A wide (water

is 2.8 A). Passage is lined with hydrophobic aa that

help exclude other small charged molecules.

Predicts one water molecule passes through at a time.

Hydrogen bond between molecules is transferred to two asparagine molecules.

Fig. 6.11

Prions Proteins that can change shape. And make other proteins change

their shape! As number of changed proteins

increases a phenotype is observed. Causal agent of mad cow disease,

scrapie in sheep and Creutzfeldt-Jakob disease in humans.

Prions II Previously thought only nucleic

acid encoded changes caused disease.

Stanley Prusiner discovered prion’s ability to change other protein’s structure and won the Nobel Prize.

Sup35 is a prion-like protein in yeast.

Sup35 Translation termination factor Carboxyl end binds to the ribosomal

complex to terminate translation. If Sup35 is converted to an alternate

conformation (infectious prion conformation) the shape change spreads throughout the cell and is passed to daughter cells.

Sup35 In prion conformation causes

ribosomes to read through stop codons altering shape and function of proteins.

Fig. 6.13 Not adaptively advantageous so

why is it maintained?

Why? True et al. 2000. Nature 407: 477-

483. Reduced translation fidelity, extends

proteins. Some of these are antibiotic resistant. Could lead to stabilization of new

phenotype under correct environment.

Introduction to Bioinformatics www.oup.com/uk/lesk/bioinf