protein physics lectures 22-23 protein structure prediction from its amino acid sequence: homology...
TRANSCRIPT
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PROTEIN PHYSICSPROTEIN PHYSICS
LECTURES 22-23LECTURES 22-23
PROTEIN STRUCTURE PREDICTIONPROTEIN STRUCTURE PREDICTION
FROM ITS AMINO ACID SEQUENCE:FROM ITS AMINO ACID SEQUENCE:
HomologyHomologySecondary structureSecondary structure
TertiaryTertiary structure structure
BIOINFORMATICSBIOINFORMATICS
PROTEIN ENGINEERING AND DESIGNPROTEIN ENGINEERING AND DESIGN
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HomologyHomology
-- - - -- - - -- - -
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SEQUENCE ALIGNMENT: SMITH-WATERMAN, BLAST,…SEQUENCE ALIGNMENT: SMITH-WATERMAN, BLAST,…
PREDICTION FROM PREDICTION FROM
HOMOLOGYHOMOLOGY
SIMILAR SEQUENCES SIMILAR SEQUENCES
SIMILAR FOLDSSIMILAR FOLDS
____________ __________________ _________________________ _______
ACCURACY ACCURACY == tt // ((tt++ ff))
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N0N0 TWILIGHTTWILIGHT ======= GOOD PREDICTION ======= ======= GOOD PREDICTION =======
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Low but existing homology.Low but existing homology. Sequence identity: 15% Sequence identity: 15%
High homology:High homology:
NO homology.NO homology. Sequence identity: 15% Sequence identity: 15%
PREDICTION FROM HOMOLOGYPREDICTION FROM HOMOLOGY
““TWILIGHT ZONE”: 10-25% IDENTITY:TWILIGHT ZONE”: 10-25% IDENTITY:
cytochromes cytochromes cc
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MultipleMultiple homology homology
key siteskey sites(core, 2(core, 200 structure, active site) structure, active site)
““PROFILES”PROFILES”““HIDDEN MARKOV MODELS” (HHMer)HIDDEN MARKOV MODELS” (HHMer) etc.etc.
BIOINFORMATICSBIOINFORMATICS
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Multiple homologyMultiple homology
PROFILEPROFILE
TARGETTARGET ......AA PP GG DD EE FF GG -- -- HH II KK KK LL MM AA AA TT CC......
SEQUENCESEQUENCE
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PREDICTION PREDICTION
FROM FROM
PHYSICS:PHYSICS:
PROTEIN CHAINPROTEIN CHAIN
FOLDSFOLDS
SPONTANEOUSLYSPONTANEOUSLY
SEQUENCE HASSEQUENCE HAS
ALL INFO TOALL INFO TO
PREDICT:PREDICT: 22O O STRUCTURE,STRUCTURE,
3D 3D STRUCTURE,STRUCTURE,SIDE CHAIN ROTAMERS,SIDE CHAIN ROTAMERS,
S-SS-S BONDS, etc. BONDS, etc.
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PREDICTION FROM PHYSICSPREDICTION FROM PHYSICS
(OR PROTEIN STATISTICS)(OR PROTEIN STATISTICS)
22O O STRUCTURESSTRUCTURES
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nonoСС(Gly)(Gly): coil: coil
СС, , 1 1 : : , , , , coilcoil -- npnp - --p--- --p--
imino: coil, imino: coil, turn, turn, NN
СС, 2 , 2 : : (3 rot.)(3 rot.)
ProPro
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PREDICTION FROM PROTEIN STATISTICSPREDICTION FROM PROTEIN STATISTICS
(OR PHYSICS)(OR PHYSICS)
TEMPLATE TEMPLATE OF SUPER-SECONDARY STRUCTUREOF SUPER-SECONDARY STRUCTURE
npnp
GlyGly
--
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FLUCTUATING FLUCTUATING SECONDARY SECONDARY STRUCTURESTRUCTUREIN UNFOLDED IN UNFOLDED POLYPEPTIDE POLYPEPTIDE CHAINCHAIN
OLYGO- &OLYGO- &POLYPEPTIDES POLYPEPTIDES
ALBALB
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FLUCTUATINGFLUCTUATINGSECONDARY SECONDARY STRUCTURESTRUCTUREAT THE AT THE ““AVERAGE”AVERAGE”SURFACE OF SURFACE OF A GLOBULEA GLOBULE
ALBALB
PHD,PHD,JPRED,JPRED,PSIPRED,…PSIPRED,…
bptibpti
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A A BB C D . C D .---different------different---
Prediction, 1985 Prediction, 1985 X-ray str.,1990X-ray str.,1990
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THREADINGTHREADING
BIOINFORMATICSBIOINFORMATICS
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THREADING:THREADING:CORRECT FOLD,CORRECT FOLD,BAD ALIGNMENTBAD ALIGNMENT
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ENGINEERING & DESIGNENGINEERING & DESIGN
DOES NOT MELT !DOES NOT MELT !MOLTEN GLOBULE…MOLTEN GLOBULE…
+ ION+ ION BINDINGBINDING SOLIDSOLID
DeGrado, 1989DeGrado, 1989
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PtitsynPtitsynDolgikhDolgikhFinkelsteinFinkelsteinFedorovFedorovKirpichnikovKirpichnikov1987-971987-97
Albebetin,Albebetin,Albeferon,Albeferon,……
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non-polar: corenon-polar: corepolar: surfacepolar: surface