Intro: 3D comparisons cb1 intro 3dcompare - ROSTLAB.ORG · /113 © Burkhard Rost 3 Notation: protein structure 1D, 2D, 3D P Q I T L W Q R P L V T I K I G G Q L K E A L L D T G A D

/113© Burkhard Rost

1

title: Computational Biology 1 - Protein structure: Intro: 3D comparisonsshort title: cb1_intro_3dcompare

lecture: Protein Prediction 1 - Protein structure Computational Biology 1 - TUM Summer 2015


Protein Prediction - Part 1: Structure

1 Introduction (contd.)

2


3

Notation: protein structure 1D, 2D, 3DPQITLWQRPLVTIKIGGQLKEALLDTGADDTVL

PP PQQQYFFQVISSIVRLLSTLWWQEDRKQAKRRRPQPPPPPVVTKFVVLIITTKEKAALIVHYKKFIILVIEENGGGGGTGQQKRRPPLWWVVFKVEESKKVVGLGLLILLLLLVVDDDDDTTTTTGGGGGAAAAADDDDDDDAKESSTTVIIVIVVVIVL

1281757077

120238169200247114740

904

466268

11831

1241

292449726217

102691

140

1109760691481976248590

690

730

415371597395000

5851300

79586900

EEEEE

EEEEEE

EEEEEEE

EE

EEEEE

EEEEEE

EE

kcal/mol0 -1 -2 -3 -4 -5

1 10 20 30 40 50 60 70 80 90

1

10

20

30

40

50

60

70

80

90

1D1D 2D2D 3D3D

Doyle et al (1998) Science 280:69-77 - The structure of the potassium channel


4



1281757077

120238169200247114740

904

466268

11831

1241

292449726217

102691

140

1109760691481976248590

690

730

415371597395000

5851300

79586900

EEEEE

EEEEEE

EEEEEEE

EE

EEEEE

EEEEEE

EE

kcal/mol0 -1 -2 -3 -4 -5

1 10 20 30 40 50 60 70 80 90

1

10

20

30

40

50

60

70

80

90

1D1D 2D2D 3D3D


5



1281757077

120238169200247114740

904

466268

11831

1241

292449726217

102691

140

1109760691481976248590

690

730

415371597395000

5851300

79586900

EEEEE

EEEEEE

EEEEEEE

EE

EEEEE

EEEEEE

EE

kcal/mol0 -1 -2 -3 -4 -5

1 10 20 30 40 50 60 70 80 90

1

10

20

30

40

50

60

70

80

90

1D1D 2D2D 3D3D


Comparing 3D structures

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Blue and red similar?

Doyle et al. (1998) Science 280:69-77 - The structure of the potassium channel: molecular basis of K+ conduction and selectivity


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Similarity now cleare?

Doyle et al. (1998) Science 280:69-77 - The structure of the potassium channel: molecular basis of K+ conduction and selectivity


3D comparisons: how to?

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10

Matching shapes

© http://www.whattoexpect.com/toddler/photo-gallery/best-toys-for-toddlers.aspx#/slide-3

http://www.whattoexpect.com/toddler/photo-gallery/best-toys-for-toddlers.aspx#


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How to match?

?


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How to match?

?


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Differences for corresponding points


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15



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12

34

56

87


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12

34

56

87

Difference= d1+d2+d3...+d8= |r1a-r1b|+...+|r8a-r8b|

RMSD (root mean square deviation)=SQRT [ (r1a-r1b)2+...(r8a-r8b)2 ]=

!"#$ !,! = !!! − !!!!

!!


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12

34

56

87

12

34

56

87

!"#$ !,! = !!! − !!!!

!!


1st: find corresponding points 2nd: superimpose

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Actual algorithm inversed

!"#$ !,! = !!! − !!!!

!!


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fit now?


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Scaling easy for simple shapes

x^2+y^2=r^2


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Proteins: points are defined->no scaling

12

34

56

87

Doyle et al (1998) Science 280:69-77 - The structure of the potassium channel


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Global vs. local comparisons


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global solution 1:

global solution 2:


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cut into “units”


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cut into “units”


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trouble: where to stop?

valid “unit”for comparison?


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How to decide what is a valid unit?

??

???


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valid “unit”for comparison?

Decision upon validity


Scientifically significant:some expert says

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Valid or not?


Scientifically significant:some expert says

Statistically significant:background

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Valid or not?

background

signal


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Cut, match, compare by RMSD

!"#$ !,! = !!! − !!!!

!!


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Only Cartesian RMSD comparison?

12

34

56

87

12

34

56

87

!"#$ !,! = !!! − !!!!

!!


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2D: difference matrix

12

34

56

87

1 2 3 4 5 6 7 81

2 3 4 5 6 7 8


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Comparison 2D: differences of differences

12

34

56

87

Total of 8 x 8 differences


3D comparisons: biology

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Slides taken from Patrice Koehl, UC Davis

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Structure alignment

Patrice Koehl


1. Identify equivalent positions (residues that match in 3D) 2. find superposition independent of domain movements

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Structure alignment: two steps

Patrice Koehl UC Davies: http://nook.cs.ucdavis.edu:8080/~koehl/Classes/CSB/lecture6.pdf

© Patrice Koehl, UC Davis

http://nook.cs.ucdavis.edu:8080/~koehl/Classes/CSB/lecture6.pdf


Step 1: find corresponding points in proteins A and B d(i) are the distances between all corresponding points (typic: Calpha, all atoms)

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rmsd(A,B) = N1

i=1

N

di2

Root mean square displacement (rmsd)


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RMSD is not a metric

A similar B B similar C NOT implying: A similar C

cRMSD = 2.8 Ǻ = 0.28 nm

A

B C

cRMSD = 2.85 Ǻ = 0.285 nm


SSAP 3D alignment

Taylor & Orengo

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SSAP concept

Sik=a

m=-n

m=+n

| di,i+m - dk,k+m | A B + b

WR Taylor & CA Orengo (1989) Protein structure alignment JMB 208:1-22


45

SSAP concept

Sik=a

m=-n

m=+n

| di,i+m - dk,k+m | A B + b

WR Taylor & CA Orengo (1989) Protein structure alignment JMB 208:1-22

Problem: loss of information about direction


DALI 3D alignment

Holm & Sander

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L Holm & C Sander (1993) JMB 233:123-38

Distance matrix Alignment Algorithm: Monte Carlo on all-against-all for hexapeptides (5)

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Structural alignment: DALI

L Holm & C Sander 91993) JMB 233:123-38: Fig. 1


Vorolign 3D alignment

Birzele & Zimmer

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Fabian Birzele, Jan E Gewehr, Gergely Csaba & Ralf Zimmer (2006) Bioinformatics 23:e205-11 Dynamic programming on Voronoi environments

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Structural alignment: VOROLIGN

F Birzele, JE Gewehr, G Csaba & R Zimmer (2006) Bioinformatics 23:e205-11: Fig. 2


3D comparisons: others

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2 forms of calcium-bound Calmodulin

Two forms of calcium-bound Calmodulin:

Ligand free

Complexed with trifluoperazine




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Global alignment: RMSD =15 Å /143 residues

Local alignment: RMSD = 0.9 Å/ 62 residues




SSAP WR Taylor & CA Orengo 1989 JMB 208:1-22 DALI L Holm & C Sander 1993 JMB 233:123-38 STRUCTAL S Subbiah, DV Laurents M Levitt 1993 Curr Biol 3:141-8 CE IN Shindyalov & P Bourne 1998 Prot Engng 1:739-47 VAST JF Gibrat, T Madej, SH Bryant 1996 Curr Opin Struct Biol 6:377-85 LSQMAN GJ Kleywegt 1996 Acta Crystallogr. D 52:842-57 SSM E Krissinel & K Henrick 2004 Acta Crystallogr. D 60:2256-68 SKAN A Yan, D Petrey & B Honig, unpublished …

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Structure alignment methods


Rachel Kolodny, Patrice Koehl, Michael Levitt

R Kolodny, P Koehl & M Levitt (2004) Comprehensive Evaluation of Protein Structure Alignment Methods: Scoring by Geometric Measures JMB 346:1173-88

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Comparison of structure alignments

Rachel Kolodny Univ of Haifa

Patrice Koehl UC Davis

Michael Levitt Stanford Univ


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How to assess 3D comparisons? standard-of-truth?

??

???


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dashed lines: original method solid lines: SAS measure

R Kolodny, P Koehl & M Levitt (2004) JMB 346:1173-88 (Fig. 1A)


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dashed lines: original method solid lines: SAS measure

R Kolodny, P Koehl & M Levitt (2004) JMB 346:1173-88 (Fig. 1A)

Best-of-All


3D comparisons: protein space and databases

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Structural universe

B Rost 1998 Structure 6:259-263

© Burkhard Rost /113

Unit of the universe: a domain

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3D modules

Multiple 3D alignment identifies consensus secondary structure


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Guessing domains from sequence

protein Aprotein Bprotein Cprotein Dprotein Eprotein F

domain 1 domain 2


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Structural universe



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Evolution of pieces

© Andrei Lupas MPI Tuebingen


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Structure evolves without leaps?

© Nick V Grishin HHMI + Univ Dallas

Fig. 1: NV Grishin 2001 NAR 29:638-43


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Structural universe: no islands, really



Similar 3D -> Similar function Learn from 3D about function Learn about evolution

classify

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3D classifications: goals


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3D modules


© C

hrist

ine O

reng

o


some structures more often observed than others limited number of shapes? fold remains an assumption (that increasingly seems to be proven inappropriate)

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Fold of a protein


© C

hrist

ine O

reng

o


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Protein structure comparisons

1bww3sdh 1xne

All-alpha All-beta AlphaBeta


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How to recognize the similarity?


SCOPhttp://scop.mrc-lmb.cam.ac.uk/scop/[A Murzin et al. (1995) JMB 247, 536-540]

CATHhttp://www.cathdb.info/[AL Cuff et al. (2009) NAR 37, D310-314; CA Orengo et al. (1997) Structure 15, 1093-1108]

COPS - QSCOP - TopMatchhttp://cops.services.came.sbg.ac.at[SJ Suhrer et al. (2009) NAR 37, W539-W44. ]

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3D classification databases

http://scop.mrc-lmb.cam.ac.uk/scop/

http://cathwww.biochem.ucl.ac.uk/latest/


Classify protein structure: SCOP

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SCOPhttp://scop.mrc-lmb.cam.ac.uk/scop/[Murzin et al. J. Mol. Biol. 247, 536-540]

hierarchy

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Protein structure comparisons

1bww3sdh 1xne



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SCOP hierarchy

SCOP

classa.

Example

{All-alpha}

Structure similarity increases


alpha beta alpha and beta (a/b – interspersed) alpha plus beta (a+b – segregated) multidomain proteins membrane and cell-surface proteins small proteins coiled coil proteins low-resolution protein structures peptides designed proteins

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SCOP classes


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SCOP class

1sw0-TIM beta/alpha barrelNAD(P)-binding Rossmann-fold domains 1sw0-TIM

CLASS = alpha and beta (a/b)


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SCOP hierarchy

SCOP

fold

classa.

Example

a.1

{All-alpha}

{Globin-like} Structure similarity increases


same major secondary structures • in the same arrangement • with the same topological connections peripheral elements may differ

• up to 50% peripheral • Turns and secondary structure elements evolutionary relationship unclear

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SCOP fold definition


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SCOP fold

CLASS = alpha and beta (a/b) FOLD = TIM beta/alpha-barrel


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Structural universe: no islands, really



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SCOP hierarchy

SCOP

fold

superfamily

classa.

Example

a.1

a.1.2

{All-alpha}

{Globin-like}

{alpha-helical ferrodoxin}

Structure similarity increases


probable common evolutionary origin low similarities, but

• share the same fold • have similar functions

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SCOP superfamily definition


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SCOP hierarchy

TRIOSEPHOSPHATE ISOMERASE (1swo)

QUINOLINIC ACID PHOSPHORIBOSYLTRANSFERASE (1qap)

PHOSPHATE ALDOLASE (1p1x )


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SCOP hierarchySCOP

family(sequence based)

c.1.1.1{Triosephosphate isomerase}

Structure similarityincreasessuperfamily

Example

c.1.1{ Triosephosphate isomerase}

fold

classc

c.1{TIM beta/alpha-barrel}

{Alpha and beta a/b}


clearly evolutionary relation Sequence identity often >30%,but not necessarily, e.g. globins: < 15% sequence identity for some members

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SCOP family definition



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Classify protein structure: CATH

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Chr is t ine Orengo (S t ruc tu res , 1997 , 5 , 1093 -1108)

Christine Orengo et al. 1997 Structures 5 1093-1108

Chr is t ine Orengo (S t ruc tu res , 1997 , 5 , 1093 -1108)

Universe of protein structures


Class Architecture Topology Homology

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CATH


Class: mostly alpha, mostly beta, mixed alpha/beta, few regular secondary structure

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CATH

1bww3sdh 1xn



Class: mostly alpha, mostly beta, mixed alpha/beta, few regular secondary structure Architecture: classification according to overall shape, ignoring connectivity Topology: fold groups = shape & connectivity Homology: evolutionarily related superfamily

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CATH


folds 1,282 superfamilies 2,549 sequence families 11,330 domains 24,232

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CATH stats (2011/05)


Find domain

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CATH: steps involved


© C

hrist

ine O

reng

o


Find domains • ab initio: consensus of three methods:

DETECTIVE:hydrophobic interiorPUU:likely separation motionDOMAK:count internal and external contactsProblem: only 20% consistent!

• Based on prior knowledge: CATHEDRAL GT: secondary structure matchingDDP: structural alignment

97


Redfern,O.C. et al. (2007) PLoS Comp. Biol., 3, e232


Find domain From domain to superfamily

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Ⓒ CATH tutorial (www.cathdb.info)

PDB id: 1gcq

(SH3 domains)

PDB id: 1gcqA0

(SH3 domain)


Find domain From domain to superfamily

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Ⓒ CATH tutorial (www.cathdb.info)

PDB id: 1gcqA0

(SH3 domain)

http://www.cathdb.info/domain/1gcqA00

http://www.cathdb.info/domain/1gcqA00


at 80% residue domain overlap: 70% of proteins in PDB have similar domains

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CATH vs SCOP

G Csaba et al. (2009) Systematic comparison of SCOP and CATH: a new gold standard for protein structure analysis. BMC Struct Biol 9:23.


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CATH: 50 structures - 1 superfamily

Ⓒ CATH

superfamily 3.40.640.10

Type I PLP-dpenedent aspartate aminotransferase-like (Major domain)


102Ⓒ Christine Orengo

Rank by family size

Perc

enta

ge o

f al

l dom

ain

sequ

ence

s

Structural families (i.e. one or more solved structures CATH/SCOP)

BIG families (currently Pfam)

Remaining families (new BIG)




103


Christine Orengo

Janet Thornton




Classify protein structure:

COPS/QSCOP/TopMatch

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COPS = Classification Of Protein Structures Based on quantified structural comparison 2007: additional info for SCOP domains: qSCOP 2009: workbench based on PDB chains: TopSearchhttp://topsearch.services.came.sbg.ac.at/

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COPS hierarchy

SJ Suhrer et al. & M Sippl (2009) COPS--a novel workbench for explorations in fold space. Nucl Acids Res 37:W539-44.

http://topsearch.services.came.sbg.ac.at


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COPS metric

Triangle inequality/transitivity:A≈B (A similar to B) B≈C (B similar to C)

⇏ B≈C (does not imply: A similar to C)

protein Aprotein Bprotein C


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PDB updates 2008/08/19-2009/04/14

SJ Suhrer et al. (2009) NAR 37:W539-W544

novelty:


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PDB diversity in light of COPS



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COPS domain parsing


Apaf-1 PDB id 1z6t

COPS c1z6tA1 (CARD domain) - c2a5yB1

c1z6tA2 (α/β domain) -

c2a5yB

c1z6tA3 (helical domain

I) - c2a5yB3

c1z6tA4 (winged-helix domain) -

c2a5yB4


110

COPS domain parsing


PDB id 1z6t-Awith 2a5y-B


No domain decomposition But:

• Complete structure comparisons

• Biological units • New metric

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COPS <-> TopSearch

MJ Sippl & M Wiederstein (2012) Detection of spatial correlations in protein structures and molecular complexes. Structure 20:718-28


SCOPhttp://scop.mrc-lmb.cam.ac.uk/scop/[A Murzin et al. (1995) JMB 247, 536-540] CATHhttp://www.cathdb.info/[AL Cuff et al. (2009) NAR 37, D310-314; CA Orengo et al. (1997) Structure 15, 1093-1108] COPShttp://cops.services.came.sbg.ac.at[SJ Suhrer et al. (2009) NAR 37, W539-W44. ]

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Manfred Sippl Salzburg




SCOPhttp://scop.mrc-lmb.cam.ac.uk/scop/A Murzin et al. 1995 JMB:247, 536-540

CATHhttp://www.cathdb.info/AL Cuff et al. 2009 NAR 37:D310-314; CA Orengo et al. 1997 Structure 15:1093-1108

COPShttp://cops.services.came.sbg.ac.atSJ Suhrer et al. 2009 NAR 37:W539-W44

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Alexey Murzin et al, Cambridge UK

Christine Orengo & Janet Thornton

et al, UCL UK

Manfred Sippl et al. Salzburg



Documents

Intro: 3D comparisons cb1 intro 3dcompare - ROSTLAB.ORG · /113 © Burkhard Rost 3 Notation: protein structure 1D, 2D, 3D P Q I T L W Q R P L V T I K I G G Q L K E A L L D T G A D