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Protein Homologue Clustering Protein Homologue Clustering and Molecular Modelingand Molecular Modeling
L. Wang
BackgroundBackground
Project done in Mt. Sinai School of Medicine, New York City.
Lab of Dr. Roberto Sanchez.A major aim of this project is to answering:
how accurate are the protein structure models from Comparative Modeling?
Protein Structure and FunctionProtein Structure and Function
Protein function is largely decided by its 3D structure
3D structure is from 1D sequence foldingProtein structure can be determined by
experimental methods, X-ray, NMROr predicted by modeling
What is Comparative ModelingWhat is Comparative Modeling
Many protein structures are similarProteins sharing at least 30% sequence
identity are generally similar to each other, and considered as homologues
Building target protein structure model based on a template protein structure already known
How to Comparative ModelingHow to Comparative Modeling
Find template Get Alignment of
target and template Based on 3-D
structure of template protein
Build model structure of target protein
Accuracy of the Comparative ModelAccuracy of the Comparative Model
1. The structural difference between the target and templates
2. The alignment between target and templates
Effect of Genome Project Effect of Genome Project
Generated a lot of protein that we know the sequence but not the structure (need)
Generated more experimental structures (template)
By programs like psi-blast, more remote homologues can be determined (coverage)
Larger database helps more accurate alignment (accuracy)
Modeller, an implementation Modeller, an implementation of Comparative Modelingof Comparative Modeling
Use scripts to control its behavior Can perform a lot of tasks from aligning,
to model building Modeller can be easily automated.
Project OverviewProject Overview
Building protein homologues using single linkage clustering algorithm
Automatically align target and template and building 3-D protein models
Comparing the models with the experimental structure
Single Linkage Method vs Single Linkage Method vs Total LinkageTotal Linkage
Coverage FactorCoverage Factor
Building Protein Homologue Building Protein Homologue ClusterCluster
From PDB, run BlastBuild tableGet first clusterFind representativesRunning PsiBlast on representativesBuild second tableMerge groups and get final cluster
(1) Refer to Duba, R.O., et al’s “Pattern Classification”, P566.
PDB Chains Unique Chains Blast
Find Representatives
Psi-blast
Re-cluster & Merge Groups
Final Cluster
Pickup X-ray Data (<=2.5Å)Nice Group Keep the Representative
Cluster (90% coverage,e-value<10-4., single linkage (1) )
Find Representative
Homologue cluster
Building models (pair-wise align. & 3-D align.)
Using the good X-ray structures
Comparing the models with the experimental structures
Error source:Alignment, plus structure difference between target and
template