Protein Structure Prediction - MMTSB · 2006-08-02 · Ab initio Structure Prediction Protocol...

MMTSB/CTBP Summer Workshop © Michael Feig, 2006.

Protein Structure Prediction

Michael FeigMMTSB/CTBP

2006 Summer Workshop


From Sequence to Structure

SEALGDTIVKNA…


Ab initio Structure Prediction Protocol

Conformational Sampling… to generate native-like structures

Scoring & Clustering… to identify most native-like structures

Amino Acid Sequence

3D Structure


Folding with All-Atom Models

CHARMM force fieldImplicit solvent replica exchange simulations8 replicas, 10 ns/replica

AAQAAAAQAAAAQAA


Folding with Low-Resolution Model

SICHO model, MONSSTER simulated annealing run

EQQNAFYEILHLPNLNEEQRNGFIQSLKDDPSQSANLLAEAKKLNDAQA


SICHO Lattice Model

Kolinski & Skolnick: Proteins 32, 475 (1998)

Monte Carlo simulations:

> Attempt move

> Compute ΔE

> Accept with probability p:

Simulated annealing

Constant Temperature

Replica Exchange Sampling

LeuThr

Asp

Phe

!

p =1 "E # 0

exp($"E /kBT ) "E > 0

% & '


SICHO Energy FunctionKnowledge-Based Terms

Excluded volume

Side chain burial propensity

follows Kyte-Doolittle scale

4.5Ile-3.5Asp-4.5Arg

1.8Ala

Centrosymmetric bias

rg = 2.2 Nres0.38


SICHO Energy FunctionStatistical Terms

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

0 1 2 3 4 5 6 7 8 9 10 11

GLU-GLU r(i,i+4) in Å

ener

gy

helixextended

Potential of mean force (PMF):

!

"E = #kT ln(p)

!

pi

p j

= e"#Eij

kBT


Conformational Sampling with SICHOProtein A

-3400

-3350

-3300

-3250

-3200

1 2 3 4 5 6 7 8 9 10 11 12

RMSD from native in Å

All-

Ato

m E

nerg

y in

kca

l/m

ol


Ab initio Structure Prediction Protocol

Efficient Samplinge.g. MONSSTER/SICHO

All-Atom Reconstruction

Scoring & Clusteringe.g. MMGB/SA, DFIRE

Secondary Structure PredictionPSIPRED et al.

Amino Acid Sequence

3D Structure


Secondary Structure Prediction

…GDPIVKNAKLDSRLANKEALRLL…

?


Secondary Structure Propensities

Chou & Fasman (1974)

α-helix β-sheet turn


Secondary Structure Prediction Methods

C+F: Chou & FasmanGOR: Garnier, Osguthorpe, Robson

77.6%SABLE

75.1%PSSP

50-60%C+F

72.3%PHD

76.1%SAM-T99-sec

76.2%PSIPRED


Secondary structure predictionPer-Residue Accuracy


Realistic ab initio Structure Prediction

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14

C! RMSD in Å (62 residues)

CHAR

MM

22/G

BMV.

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.


-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.

Sampling, Scoring, Clustering

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.

-2750

-2700

-2650

-2600

-2550

-2500

-2450

-2400

6 7 8 9 10 11 12 13 14


CHAR

MM

22/G

BMV.


Ab initio PredictionsDNase fragmentation factor

Best-scoring prediction 7.4 Å RMSD

NMR structure 1KOY


Scoring Functions

Knowledge-based/statistical derived from known protein structures limited by training data usually fast e.g. DFIRE, RAPDF, prosaII

Force field based model physical energy landscape more robust and transferable often expensive (require minimization) e.g. MMPB(GB)/SA, UNRES


Scoring Function ComparisonMMGB/SA vs. DFIRE

14.2

14.4

14.6

14.8

15

15.2

15.4

15.6

15.8

5.5 6 6.5 7 7.5 8 8.5

C! RMSD in Å

radiu

s of

gyr

atio

n

-4200

-4100

-4000

-3900

-3800

-3700

-3600

-3500

5.5 6 6.5 7 7.5 8 8.5

C! RMSD in Å

MM

GB/S

A s

core

-10500

-10000

-9500

-9000

-8500

-8000

5.5 6 6.5 7 7.5 8 8.5

C! RMSD in Å

DFIR

E s

core


Sampling with Restraints

Secondary structure bias

Secondary structure prediction

NMR shift data

Distance restraints

Experimental restraints (disulfides, NMR, EPR)

Side chain contacts from analogous structures

Shape restraints

cryoEM data, small-angle X-ray scattering


… but the solution may lieelsewhere.


Sequence Homology

SDKIIHLTDDSFDTDVLKADGAILVDFWAEWCGPCKMIAPILDEIADEYQGKLTVA : :. .. .: ..::: : :::::::: :.. .....:.. . .MVKQIESKTAFQEALDAAGDKLVVVDFSATWCGPCKMIKPFFHSLSEKYSNVIFL-

KLNIDQNPGTAPKYGIRGIPTLLLFKNGEVAATKVGALSKGQLKEFLDAN---LA....:. .: . .. .::. .::.:. ::: .: : :: :.:. :.EVDVDDCQDVASECEVKCMPTFQFFKKGQ----KVGEFS-GANKEKLEATINELV

Human thioredoxin (1AUC)

E. Coli thioredoxin (1THO)


Comparative Modeling

Human thioredoxin (1AUC)

E. Coli thioredoxin (1THO)

Assumption: Proteins with similar sequence have similar structure


Structural Templates from Homology

Challenges:

Correct alignment Loop modeling Side chain rebuilding

PGTAPKYGIRGIPTLLLFKNGEVAATKVGALSKGQLKEFLDAN---LA .: . .. .::. .::.:. ::: .: : :: :.:. :.QDVASECEVKCMPTFQFFKKGQ----KVGEFS-GANKEKLEATINELV


Accuracy of Predictions by Homology

0

20

40

60

80

100

20 30 40 50 60 70 80 90 100

% sequence identity

% p

red

icti

on

s

<2Å RMSD

<5Å RMSD


Prediction through Fold Recognition

Assumption: Proteins with similar secondary structure share fold

1N91 1JRM


Templates through Fold Recognition

Challenges:

Wrong templates Alignment uncertain Fragment modeling Refinement needed


Ab initio Sampling in Template-basedStructure Prediction

Template provides known protein structure

Ab initio sampling of unknown fragments in the context of template


Template Restraints Near Flexible Part

0.10.2

0.40.7

0.0

1.0

Restraint potential:

!

U = f " k(r # r0)2


Loop Sampling Methods

MMTSB Tool SetAll-Atom Reconstruction1-2

Rosetta (Baker)Fragment-based2-100MMTSB Tool SetMulti-Scale5-30Modeller (Sali)Torsional Space MC/MD2-12

Exhaustive Search1-3

ProgramSampling# Residues


Structural Genomics Efforts


Structure Refinement

predicted native (NMR)

?

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Protein Structure Prediction - MMTSB · 2006-08-02 · Ab initio Structure Prediction Protocol...

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