protein homologue clustering and molecular modeling l. wang

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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

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