Computer Aided Drug Design ——Protein structure...
Transcript of Computer Aided Drug Design ——Protein structure...
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Computer Aided Drug Design
——Protein structure prediction
Qin Xu http://cbb.sjtu.edu.cn/~qinxu/CADD.htm
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Course Outline • Introduction and Case Study • Drug Targets
– Sequence analysis – Protein structure prediction – Molecular simulation
• Drug Design – Combinatorial library – 3D-QSAR – Statistical methods
• Molecular Docking
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Why protein structure
prediction ?
By 2014/09
The huge differences in known protein sequences, 3 dimensional structures and functions
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Why we can do protein structure prediction ?
• Sequence – From DNA/RNA sequence – Protein sequencing
• Structure – Secondary structure – Tertiary structure – Quaternary structure
• Function – Activity, specificity – Binding – Regulation
Anfinsen's dogma: the native structure of a globular proteins is determined only by the protein's amino acid sequence
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Protein structure prediction
• Secondary structure prediction – Distribution of amino acids – Featured sequenceFeatured domain
• Tertiary structure prediction
– The 3D structure of target proteins – Structure of active site, binding site,
possible conformational changes – Molecular docking, molecular dynamics
simulations
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Protein 3D structure prediction
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Protein 3D structure prediction
• Homology Modeling – Homolog template – Similar sequence similar secondary
structure similar featured domain similar backbone similar 3D structure with optimized side chains
• Threading method – Fold recognition method – Long distance homology protein
• Ab initio prediction – Sequence Structure – Conformer search – Energy minimization
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Basic steps in homology modeling
BLAST, FASTA, PSI-BLAST,… http://blast.ncbi.nlm.nih.gov/Blast.cgi http://www.ebi.ac.uk/Tools/sss/fasta/ CLUSTAL,…
http://www.ebi.ac.uk/Tools/msa/clustalw2/
PROCHECK, VERIFY3D,… http://www.ebi.ac.uk/thornton-srv/software/PROCHECK/ http://nihserver.mbi.ucla.edu/Verify_3D/
Modeling MODELLER, SWISS-MODEL http://salilab.org/modeller/, swissmodel.expasy.org/
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Homology Modeling with SWISS-MODEL http://www.expasy.org/swissmod/SWISS-MODEL.html
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Homology Modeling with SWISS-MODEL Search for Templates
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Homology Modeling with SWISS-MODEL
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Homology Modeling with SWISS-MODEL UniProt AC
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Homology Modeling with SWISS-MODEL UniProt AC
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Homology Modeling with SWISS-MODEL Known template
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Homology Modeling
with SWISS-MODEL
Results
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Homology Modeling with MOE
• MOE – Molecular Operating Environment – http://www.chemcomp.com/ – Current release: MOE2013.08
• SAMM – Shanghai Molecular Modeling
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Forcefield setup
MMFF94x (default): small molecules and compounds
Amber99, CHARMM27, OPLS-AA: macromolecules, proteins MOE|Window|Potenial Setup…Load
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Searching templates
• Target 69 of CASP4
SE|Homology|PDB Search
SE|File|Open…
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Searching templates
SE|Display|Actual Secondary Structure
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Alignment
SE|Homology|Align
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Sequence identity key factor for the accuracy
SE|window|Commands
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% structure overlap the fraction of equivalent residues (Cα atoms within 3.5Å each other).
Sequence identity and Model precision
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Sequence identity and Model accuracy
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Sequence identity and applications
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Homology modeling
SE|Homology|Homology Model
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Models in database
SE|File|Open…
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Secondary structures of Models
SE|Display|Actual Secondary Structure
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3D Structures of Models backbones variations at a loop
Database Viewer (right click on models)
Copy selected to MOE
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3D Structures of Models detailed variations at a loop
SE|Selection|Residues|With Selected Atoms
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Model Evaluation
Ramachandran Plot (Phi-Psi Plot) Dihedrals MOE|Compute|Biopolymer|Protein Geometry
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Report on outliers
Export Report
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Select and View outliers
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Binding site MOE|Compute|Site finder
MOE|Compute|Surface and Maps
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Course Outline • Introduction and Case Study • Drug Targets
– Sequence analysis – Protein structure prediction – Molecular simulation
• Drug Design – Combinatorial library – 3D-QSAR – Statistical methods
• Molecular Docking