Protein Homology Modelling：蛋白质同源建模.ppt

Protein Homology Modelling Thomas Blicher Center for Biological Sequence Analysis Learning Objectives After this lesson you should be able to: Explain the individual steps involved in calculating a protein homology model. Identify suitable templates for modelling. Outline the principles behind ab initio protein structure prediction. Describe the differences between homology modelling and ab initio structure prediction. Describe the major pitfalls in protein modelling. Outline Protein homology modelling Individual steps Caveats Pitfalls Ab initio protein structure prediction Threading True ab initio methods How Is It Possible? The structure of a protein is uniquely determined by its amino acid sequence(but sequence is sometimes not enough): prions pH, ions, cofactors, chaperones Structure is conserved much longer than sequence in evolution. Structure Function Sequence How Often Can We Do It? There are currently ~47000 structures in the PDB (but only ~4000 if you include only ones that are not more than 30% identical and have a resolution better than 3.0 ?). An estimated 25% of all sequences can be modeled and structural information can be obtained for ~50%. Worldwide Structural Genomics Structural Genomics in North America 10 year $600 million project initiated in 2000, funded largely by NIH. AIM: structural information on 10000 unique proteins (now 4-6000), so far 1000 have been determined. Improve current techniques to reduce time (from months to days) and cost (from $100.000 to $20.000/structure). 9 research centers currently funded (2005), targets are from model and disease-causing organisms (a separate project on TB proteins). Homology Modeling for Structural Genomics How Well Can We Do It? How Is It Done? Identify template(s) – initial alignment Improve alignment Backbone generation Loop modelling Side chains Refinement Validation ? Template Identification Search with sequence Blast Psi-Blast Fold recognition methods Use biological information Functi