From protein structure to function

The particular catalytic activity, binding properties or conformational changes of a protein.

The complex, or metabolic or signal transduction pathway in which a protein participates

Gene duplication – with two copies of a gene, one can retain its function while the other can assume a new biological role.

Gene fusion – two genes are combined and activated by the same promoter

One Gene – to or more functions Post translational modifications Alternate splicing

With high throughput crystallization techniques, structure can be determined more easily than function

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sequence idenity (%)

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Conservation of Enzyme Function in CATH Domain FamiliesConservation of Enzyme Function in CATH Domain Families

Pairwise sequence identity

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uct

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Build a interaction network Model response of gene to changes in

promoter concentration Simulate the system to determine

influence of gene product on system

Complex systems of simple elements have functions that emerge from the properties of the networks they form.

Biological systems have functions that rely on a combination of the network and the specific elements involved.

In molecular biology, gene structure and function is studied at the molecular level.

In systems biology, specific interactions of components in the biological system are studied – cells, tissues, organs, and ecological webs.

Biological Systems are complex, thus, a combination of experimental and computational approaches are needed.

Linkages need to be made between molecular characteristics and systems biology results

Languages Systems Biology Markup Language CellML Systems Biology Workbench

Databases Kyoto Encyclopedia of Genes and Genomes Alliance for Cellular Signaling Signal Transduction Knowledge Environment

Protein 53 Guardian of the genome Detects DNA damages Halts the cell cycle if damage is detected

to give DNA time to repair itself

If (damage equals true and repairable = true)

halt cell cycle else

if(damage equals true and repairable = false) induce apoptosis (suicide)

G1 - Growth and preparation of the chromosome replication

S - DNA replication

G2 - Preparation for Mitosis

M - Chromosomes separate

ataxia-telangiectasia mutated

p53activates

p21deactivates

CDK

No cell cycle!

Alkylating agents - interfere with cell division and affect the cancer cells in all phases of their life cycle. They confuse the DNA by directly reacting with it.

Antimetabolites - interfere with the cell's ability for normal metabolism. They either give the cells wrong information or block the formation of "building block" chemical reactions one phase of the cell's life cycle.

Vinca alkaloids - (plant alkaloids) are naturally-occurring chemicals that stop cell division in a specific phase.

Taxanes - are derived from natural substances in yew trees. They disrupt a network inside cancer cells that is needed for the cells to divide and grow.

all inhibit the cell cycle

Once you have simulated gene regulatory networks, build organ or organism models

NOBLE, D (2002) Nature Reviews Molecular Cell Biology 3, 460-463.

Unravelling complexityNeed to work in an integrative way at all levels:

organism organtissue

cellular sub-cellularpathwaysprotein

gene

There are feed-downs as well as upward between all these levels

higher levels controlgene expression

higher levels controlcell function &

pathways

Heart Model Construction 2000

INa

IClIK1 IK Ito

ICa

Channels

I Na/K

I NaCaNa/H Na/HCO3 Cl/OH

Cl/HCO3

Carriers

Ca

pH

ATP

Glucose

Fatty Acids

Amino Acids

H/Lactate

SubstratesAng II1

2

NO

ßM

Receptors

Example of protein interaction in a cell model Reconstructing the heart’s pacemaker

Sinus rhythm generated by ion channel interaction

ICaL

IKr

Em

If is example of fail-safe ‘redundancy’

Rhythm abolished when interaction prevented

Acceleration of sinus rhythm by adrenaline

If

All 3 protein levels up-regulated

Disease insightModelling arrhythmias

Mutations in various ionic channels can predispose to repolarization failure

This simulation is of a sodium channelmis-sense mutation responsible foridiopathic ventricular fibrillation

Expressed sodium channel kinetics(Chen et al, Nature, 19 March 1998)

Computer model prediction

• Sodium channel missense mutation

• 12 and 18 mV voltage shifts

• Using digital cell ventricular model

12 mVshift18 mVshift

This approach has now been used for a substantial number of gene manipulations in heart cells and can account for genetic susceptibility to fatal cardiac arrhythmia

Including interactions with drugs causing long QT and arrhythmia in clinical trials

Genetic typing to screen out those susceptible to drugs causingQT problems is therefore a foreseeable possibility

Noble D (2002) Unravelling the genetics and mechanisms of cardiac arrhythmia. Proc Natl Acad Sci USA 99, 5755-6

Unravelling genetics of arrhythmia

http://thevirtualheart.org http://www.math.nyu.edu/~griffith/heart_anim Systems biology and the heart Modeling the Heart--from Genes to Cells to the

Whole Organ http://domino.research.ibm.com/comm/

research_projects.nsf/pages/cancermodeling.index.html