protein physics lectures 22-23 protein structure prediction from its amino acid sequence: homology...
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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
HomologyHomology
-- - - -- - - -- - -
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))
N0N0 TWILIGHTTWILIGHT ======= GOOD PREDICTION ======= ======= GOOD PREDICTION =======
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
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
Multiple homologyMultiple homology
PROFILEPROFILE
TARGETTARGET ......AA PP GG DD EE FF GG -- -- HH II KK KK LL MM AA AA TT CC......
SEQUENCESEQUENCE
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.
PREDICTION FROM PHYSICSPREDICTION FROM PHYSICS
(OR PROTEIN STATISTICS)(OR PROTEIN STATISTICS)
22O O STRUCTURESSTRUCTURES
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
PREDICTION FROM PROTEIN STATISTICSPREDICTION FROM PROTEIN STATISTICS
(OR PHYSICS)(OR PHYSICS)
TEMPLATE TEMPLATE OF SUPER-SECONDARY STRUCTUREOF SUPER-SECONDARY STRUCTURE
npnp
GlyGly
--
FLUCTUATING FLUCTUATING SECONDARY SECONDARY STRUCTURESTRUCTUREIN UNFOLDED IN UNFOLDED POLYPEPTIDE POLYPEPTIDE CHAINCHAIN
OLYGO- &OLYGO- &POLYPEPTIDES POLYPEPTIDES
ALBALB
FLUCTUATINGFLUCTUATINGSECONDARY SECONDARY STRUCTURESTRUCTUREAT THE AT THE ““AVERAGE”AVERAGE”SURFACE OF SURFACE OF A GLOBULEA GLOBULE
ALBALB
PHD,PHD,JPRED,JPRED,PSIPRED,…PSIPRED,…
bptibpti
A A BB C D . C D .---different------different---
Prediction, 1985 Prediction, 1985 X-ray str.,1990X-ray str.,1990
THREADINGTHREADING
BIOINFORMATICSBIOINFORMATICS
THREADING:THREADING:CORRECT FOLD,CORRECT FOLD,BAD ALIGNMENTBAD ALIGNMENT
ENGINEERING & DESIGNENGINEERING & DESIGN
DOES NOT MELT !DOES NOT MELT !MOLTEN GLOBULE…MOLTEN GLOBULE…
+ ION+ ION BINDINGBINDING SOLIDSOLID
DeGrado, 1989DeGrado, 1989
PtitsynPtitsynDolgikhDolgikhFinkelsteinFinkelsteinFedorovFedorovKirpichnikovKirpichnikov1987-971987-97
Albebetin,Albebetin,Albeferon,Albeferon,……
non-polar: corenon-polar: corepolar: surfacepolar: surface