Transcript Orengo-10
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 Conservation of Enzyme Function in CATH Domain Families 90 80 SSAP score Structural similarity (SSAP) score 100 Different Function Same Function 70 60 50 40 0 10 20 30 40 50 60 70 80 90 100 sequence idenity (%) Pairwise sequence identity same functions different functions 90 80 SSAP score Structural similarity (SSAP) score 100 Different Function Same Function 70 60 50 40 0 10 20 30 40 50 60 70 80 90 100 sequence idenity (%) Pairwise sequence identity same functions different functions 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 p53 activates p21 deactivates No cell cycle! CDK 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 complexity Need to work in an integrative way at all levels: higher levels control cell function & pathways organism organ tissue cellular sub-cellular pathways protein gene higher levels control gene expression There are feed-downs as well as upward between all these levels Heart Model Construction 2000 Channels Receptors IK1 IK Ito ICl ICa Ang II ß1 M2 INa Substrates Glucose NO Fatty Acids Ca ATP Amino Acids pH H/Lactate I Na/K I NaCa Na/H Na/HCO3 Carriers Cl/OH Cl/HCO3 Example of protein interaction in a cell model Reconstructing the heart’s pacemaker Sinus rhythm generated by ion channel interaction Acceleration of sinus rhythm by adrenaline Em IKr ICaL Rhythm abolished when interaction prevented All 3 protein levels up-regulated If is example of fail-safe ‘redundancy’ Disease insight Modelling arrhythmias Mutations in various ionic channels can predispose to repolarization failure This simulation is of a sodium channel mis-sense mutation responsible for idiopathic 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 18 mV mV shift shift Unravelling genetics of arrhythmia 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 causing QT 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 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