protein structure and modelling ● orientation ● protein structure ● protein modelling andreas...
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Protein structure and modelling
● Orientation● Protein structure● Protein modelling
Andreas HegerUniversity of HelsinkiBioinformatics Group
Slides will be available at: ekhidna.biocenter.helsinki.fi:8080/downloads/teaching/hut2004/
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Proteins
● Proteins are involved in all processes inside a cell– Gene regulation– Metabolism– Signalling– Development– Structure
http://www.websters-online-dictionary.org/definition/english/ce/cell.html
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Chemistry
● Proteins are linear hetero-polymers of amino acids– twenty different amino acids (building blocks)
ARG LYS VAL ILE PRO ARG GLU LYS
R K V I P R E K
3-letter code
1-letter code
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Peptide bond
http://www.imb-jena.de/~rake/Bioinformatics_WEB/basics_peptide_bond.html
The peptide bond is planar
2 angles freely rotatable1 is fixed
Peptide ~ 2-10 amino acidsPolypeptide ~ 10-50 amino acidsProtein ~ 50- amino acids
Double bond character of the peptide bond
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Amino acids
● Side chain properties– Size– Charge– Polarity
http://www.ch.cam.ac.uk/SGTL/Structures/amino/
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Proteins are very special polymers:● A given protein has always the same amino acid
sequence– Protein sequence is determined by DNA sequence
● A given protein has always a unique three- dimensional structure.– Protein structure is determined by protein sequence.
always = biological always (there are exceptions)
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Protein evolutionSequence – Structure - Function
DNA sequence
Protein sequence Protein structure
Protein functionSelection
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Summary
● Protein structure is the key to understanding protein function
● Topics in protein structure
1.Protein structure determination
2.Protein architecture
3.Protein function
4.Protein folding● Protein modelling and computational methods
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Protein structure determination
● Protein expression– membrane proteins– aggregation
● X-Ray crystallography● NMR (nuclear magnetic resonance)● Cryo-EM (electron microscopy)
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Structures by X-ray crystallography
➔ Crystallize protein● Collect diffraction patterns● Improve iteratively:
– Calculate electron density map● Phase problem
– Fit amino acid trace through map
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X-ray crystallography
● Crystallization
● “An art as much as a science”Charges
http://crystal.uah.edu/~carter/protein/crystal.htm
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Diffraction and electron density maps
Diffraction pattern
X-ray source Crystal
Intensities
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Iterative refinement
http://www.sci.sdsu.edu/TFrey/Bio750/Bio750X-Ray.html
Higher resolution =more accurate positioning of atoms
Resolution
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NMR
● Create highly concentrated protein solution● Record spectra● Assign peaks to residues● Calculate constraints● Compute structure
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NMR spectra
1D 2D
http://www.cryst.bbk.ac.uk/PPS2/projects/schirra/html/2dnmr.htm
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Distance constraints from NMR
● From the sequence– Topology– Bond angles– Bond lengths
● From the NMR experiment– Torsion angles– Distance constraints
HαR
CO
H
CO
Torsion angle
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Ensemble of structures
SH3-domain
1aey
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What is the true protein structure?
● X-Ray– “frozen” state of a protein
● crystal contacts✔ large protein structure
● NMR✔ protein in solution– limited in size
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Molecular complexesvia X-ray
1fjg
30 S subunit of the ribosome
Protein
RNA
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Cryo-EMSingle particle image reconstruction
Koning et al. (2003)
Bacteriophage MS2
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Fitting X-Ray structures into density maps
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GroEL-complex
1gr6
Hemoglobin
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Protein structure databases
http://www.wwpdb.org/index.html
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Protein architecture
● Protein structure is the key to understanding protein function
● Topics in protein structure
1.Protein structure determination
2.Protein architecture
3.Protein function
4.Protein folding● Protein modelling and computational methods
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Topics in protein architecture
● Principles of protein architecture– Secondary structure– Supersecondary structure– Tertiary structure– Quarternary structure
● Classification of protein structures
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The big surprise
DNA is a regular structure Watson & Crick (1953)
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Myoglobin
Kendrew and Perutz1957
1mbn
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Secondary structure● backbone
– no amino acid side chains● regular patterns
– of hydrogen-bonds– backbone torsion angles
● types of secondary structure
– α-helix– β-sheet– ...
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α-Helix
β-Sheethydrogen bond pattern: n, n+4
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β-sheet
http://broccoli.mfn.ki.se/pps_course_96
view from the top view from the side
β-strands
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Cartoon representation
2TRX 2AAC
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Supersecondary structures
● local arrangments of secondary structure elements
http://www.expasy.org/swissmod/course/text/chapter2.htm
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Tertiary structure
1coh
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Quaternary structure
1coh
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Protein structure
● Primary structure
● Secondary structure
● Super-secondary structure
● Tertiary structure
● Quaternary structure
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Protein domains/modules
● globular● independently foldable● occur in different contexts
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Domains via the contact matrix
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Structure classification
● 24908 structures in the Protein Databank (PDB)● major classifications of proteins:
– SCOPhttp://scop.mrc-lmb.cam.ac.uk/scop/
– CATHhttp://www.biochem.ucl.ac.uk/bsm/cath/
– DALI DOMAIN DICTIONARY/FSSPhttp://ekhidna.biocenter.helsinki.fi:8080/dali/index.html
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Hierachical description of protein architecture
1.Class:
α, β, α/β, α+β
2.FoldStructural similarity
3.SuperfamilyEvolutionary relationship
4.FamilySequence similarity
1.Class
α, β, α&β
2.ArchitectureSS: Spatial arrangement
3.TopologySS: Topology
4.Homologystructural/sequence similarity
SCOP CATH
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CATH
http://www.biochem.ucl.ac.uk/bsm/cath/cath_info.html
Class
Architecture
Topology
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Dali Domain Dictionary
1.Fold space attractor region
Secondary structure composition and supersecondary structural motifs
2.Globular folding topology
Structural comparison
3.Functional family
Neural network
4.Sequence family
Sequence comparison
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Deviation from globularity
● Domain swapping● Repetitive structures● Open/closed conformations
1bsr
5rsa
1amy
1d0b
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Protein function
● Protein structure is the key to understanding protein function
● Topics in protein structure
1.Protein structure determination
2.Protein architecture
3.Protein function
4.Protein folding● Protein modelling and computational methods
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Topics in protein function
● How does structure determine function?– Structural proteins– Enzymes– Transcription factors– ...
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Structural proteins
● Collagen
1K6F http://www.aw-bc.com/mathews/ch06/fi6p13ad.htm
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Actin and muscles
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Enzymes
● Catalytic triad: Asp, Ser, His
1CHO
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Mechanism
● Enzymes speed up chemical reactions● Enzymes are not consumed by the reaction● Stabilization of the transition state● Charge-relay cascade
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Convergent evolution in serine proteases
● same reaction● same mechanism● same orientation of
catalytic residues● different structures
– Chymotrypsin:● His-57, Asp-102, Ser-195
– Subtilisin:● Asp-32, His-64, Ser-221
1cho / 1sib
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Substrate specificity
Perona & Craik (1997)
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Transcription factors
1L3L
Ligand
DNA
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Hydrogen bonding pattern
Vannini (2002)
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Protein folding
● Protein structure is the key to understanding protein function
● Topics in protein structure
1.Protein structure determination
2.Protein architecture
3.Protein function
4.Protein folding● Protein modelling and computational methods
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Protein denaturation
● Denatured state = unfolded state● Native state = folded state● Denaturation = heat, urea, salts
Reaction coordinate
Energy
FoldedUnfolded
Reaction coordinate
Energy
FoldedUnfolded
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Protein stability
● Native state only marginally more stable than denatured state
● Contributions to protein stability– hydrophobic effect: entropic effect– hydrogen bonds: net effect = 0– others
● salt bridges● disulphide bonds● aromatic-aromatic interactions● metal binding
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Hydrophobic core of lysozyme
1HELHydrophobic amino acid
Hydrophilic amino acid
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Protein folding
● Folding Funnel● Energy landscape
guides protein towards native structure
Dobson (2004)
C: total contacts
Q: native contacts
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Energy landscape for the folding of lysozyme
Fast trackSlow track
Dobson (2004)
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Misfolded proteins
● Disulfid-isomerases, Prolin-isomerases● Chaperones: unfold misfolded proteins● Protein folding diseases
– BSE– Alzheimer's disease– Parkinson's disease– ...
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GroEL – a chaperone
1gr6
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Wang & Weissmann (1999)
Roseman et al. (1996)
GroEL mechanism
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Protein structure
● Protein structure is the key to understanding protein function
● Topics in protein structure
1.Protein structure determination
2.Protein architecture
3.Protein function
4.Protein folding● Protein modelling and computational methods