cb1e 20170504 intro2 structure - rostlab · 2017. 5. 4. · cb1_intro2_structure lecture: protein...

/108© Burkhard Rost

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title: Computational Biology 1 - Protein structure:   Intro into protein structure

short title: cb1_intro2_structure

lecture: Protein Prediction 1 - Protein structure  Computational Biology 1 - TUM Summer 2016


Videos: YouTube / www.rostlab.org  THANKS :  . EXERCISES: Special lectures: • TBD - Thomas Hopf • TBD - Jonas Reeb No lecture:• 05/10 Student assembly (SVV) • 05/17 Ascension day • 05/26 Whitsun holiday • 06/04 Corpus Christi LAST lecture: June 28 (followed by 2 wrap-up sessions) Examen: June 30, 2016: lecture time room TBD • Makeup: TBC: Oct 18 & 20, 2016 - lecture time

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CONTACT: Lothar Richter [email protected]

Dmitrij Nechaev

Lothar Richter

http://www.rostlab.orgmailto:[email protected]?subject=


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Questions about last lecture?

??

???

© Wikipedia

© Burkhard Rost

Recap

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common to life: DNA/cellsDNA->RNA->proteins = machinery of life

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Recap: genes - proteins


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Central dogma

slide: Andrea [email protected]

Structure

Function


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Codon wheel

© yourgenome.org slide: Andrea Schafferhans


run: 6 hoursfull capacity: ~5-10 TB data / day

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Illumina: MiSeq

Illumina - Early 2012


common to life: DNA/cellsDNA->RNA->proteins = machinery of lifeproteins made up of amino acids (20 different: like pearl chains with pearls of 20 different sizes & “colors”, i.e. biophysical features)20k proteins in human~85M proteins knownprotein length (number of amino acids): 35-30K

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Recap: genes - proteins


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1ej9 Topoisomerase

1i6h RNA Polymerase

1ais TATA-binding Protein/Transcription Factor IIB

1cgp Catabolite GeneActivator Protein

1tau DNA Polymerase

1lbh+1efa lacRepressor

1aoi Nucleosome

1aoi Nucleosome

1b7t Myosin 1atn Actin

1tub Microtubule1bkv Collagen

© David Goodsell

scale reduced


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Cells: outside & inside

Illustration of Mycoplasma genitalium by David S. Goodsell, the Scripps Research Institute, UCSD, USA


Previous lecture• Organisms, genes, central dogma

TODAY: Protein introduction• Amino acids • Protein structure • Bonds & energies • domains • 3D comparisons

NEXT lectures• sequence comparisons/alignments

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TOC today

© Burkhard Rost

Protein Prediction I: Beginners

1 Introduction

1.2 - Proteins/domains

1.3 - 3D comparisons

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© Burkhard Rost

Reality and images

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slide: Marco Punta


Georges Braque - Houses at L'Estaque

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slide: Marco Punta


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Where is that?

Illustration by David S. Goodsell, the Scripps Research Institute, UCSD, USA


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Mycoplasma genitalium



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Eukaryotic cell



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slide: Marco Punta


Doyle et al. (1998) Science 280:69-77 - The structure of the potassium channel: molecular basis of K+ conduction and selectivity 21

slide: Marco Punta


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http://www.proteopedia.org/wiki/images/7/7b/1htb2.png

Alcohol dehydrogenase (ADH)

PC Sanghani, H Robinson, WF Bosron, TD Hurley (2002) Biochemistry 41:10778-86

http://upload.wikimedia.org/wikipedia/commons/thumb/a/a5/Protein_ADH5_PDB_1m6h.png/800px-Protein_ADH5_PDB_1m6h.png

homodimer ADH5

http://www.proteopedia.org/wiki/images/7/7b/1htb2.pnghttp://www.proteopedia.org/wiki/images/7/7b/1htb2.pnghttp://www.proteopedia.org/wiki/images/7/7b/1htb2.pnghttp://www.proteopedia.org/wiki/images/7/7b/1htb2.pnghttp://www.proteopedia.org/wiki/images/7/7b/1htb2.pnghttp://www.proteopedia.org/wiki/images/7/7b/1htb2.pnghttp://www.proteopedia.org/wiki/images/7/7b/1htb2.pnghttp://www.proteopedia.org/wiki/images/7/7b/1htb2.png


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slide: Marco Punta


Umberto Boccioni - Dynamism of a soccer player

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slide: Marco Punta


Photograph: Filippo Monteforte/AFP/Getty Images

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slide: Marco Punta



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Different levels of abstraction

Wu et al. unpublished

Photograph: Filippo Monteforte/AFP/Getty Images slide: Marco Punta


© Burkhard Rost

Constituents of proteins: amino

acids

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CH

R

H NH

C O

OH

backbone

side-chain

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Amino acid

slide: Marco Punta


CH

R

H NH

C OH

backbone

side-chain

O

isolated amino acid

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Joining amino acids into proteins

slide: Marco Punta


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CH

R

H NH

C O

backbone

side-chain

HC

R

HN C

OH

Obackbone

side-chain

a dipeptide

From Wikipedia

slide: Marco Punta


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CH

R

H NH

C O

backbone

side-chain

HC

R

HN C

OH

Obackbone

side-chain

a dipeptide

From Wikipediawww.webchem.net/notes/chemical_bonding/covalent_bonding.htm

slide: Marco Punta

http://www.webchem.net/notes/chemical_bonding/covalent_bonding.htmhttp://www.webchem.net/notes/chemical_bonding/covalent_bonding.htm


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CH

R

H NH

C O

backbone

side-chain

HC

R

HN C

OH

Obackbone

side-chain

a dipeptide

From Wikipedia

www.webchem.net/notes/chemical_bonding/covalent_bonding.htm


slide: Marco Punta



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CH

R

H NH

C O

backbone

side-chain

HC

R

HN C

OH

Obackbone

side-chain

a dipeptide

From Wikipedia





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CH

R

H NH

C O

backbone

side-chain

HC

R

HN C

OH

Obackbone

side-chain

a dipeptide

From Wikipedia





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CH

R

H NH

C O

backbone

side-chain

HC

R

HN C

OH

Obackbone

side-chain

a dipeptide

From Wikipedia





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CH

R

H NH

C O

backbone

side-chain

HC

R

HN C

Obackbone

side-chain

CH

R

NH

C O

backbone

side-chain

HC

R

HN C

OH

Obackbone

side-chain

N’

C’

polypeptide chain


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CH

R

H NH

C OH

backbone

side-chain

O


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39



40



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Peptides

Images: https://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/protein2.htm

slide: Andrea Schafferhans

© Burkhard Rost

Rationalizing biophysical features

of constituents

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Side chain properties


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Side chain properties

+R

+K


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Negatively charged amino acids-

-D

E


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Polar amino acids

+----

++

+N

Q

S

YT


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amino acids

© Burkhard Rost

“components” of protein structure:

domains

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Domain from introns?

© Wikipedia

RNA splicing

Gene product = protein


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Domain merger

prokaryote P, protein Aprokaryote P, protein B

prokaryote P2, protein C


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3D modules

Multiple 3D alignment identifies consensus secondary structure

© C

hrist

ine O

reng

o


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3D modules


© C

hrist

ine O

reng

o


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Guessing domains from sequenceprotein Aprotein Bprotein Cprotein Dprotein Eprotein F

domain 1 domain 2


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Most proteins multi-domain

Liu, Hegyi, Acton, Montelione & Rost 2003 Proteins 56:188-200Liu & Rost 2004 Proteins 55:678-686

Single-domain proteins: 61% in PDB 28% in 62 proteomes

© Burkhard Rost

3D comparisons: principle idea

how to?

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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#http://www.whattoexpect.com/toddler/photo-gallery/best-toys-for-toddlers.aspx#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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12

34

56

87


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12

34

56

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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

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!"#$ !,! = !!! − !!!!

!!


1st: find corresponding points2nd: superimpose

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Actual algorithm inverted

!"#$ !,! = !!! − !!!!

!!


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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

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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?


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How can a machine decide what is a valid unit?

??

???


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

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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

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Total of 8 x 8 differences


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 Bd(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


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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


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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

Problem: loss of information about direction


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PQITLWQRPLVTIKIGGQLKEALLDTGADDTVL

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

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


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

Distance matrix AlignmentAlgorithm: 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


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


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2 forms of calcium-bound Calmodulin

Two forms of calcium-bound Calmodulin:

Ligand free

Complexed with trifluoperazine

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

© Patrice Koehl, UC Davis


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Global alignment: RMSD =15 Å /143 residues

Local alignment: RMSD = 0.9 Å/ 62 residues

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

© Patrice Koehl, UC Davis


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Cells: outside & inside

Illustration of Mycoplasma genitalium by David S. Goodsell, the Scripps Research Institute, UCSD, USA


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A gallery of proteins

1ej9 Topoisomerase

1i6h RNA Polymerase

1ais TATA-binding Protein/Transcription Factor IIB

1cgp Catabolite GeneActivator Protein

1tau DNA Polymerase

1lbh+1efa lacRepressor

1aoi Nucleosome

1aoi Nucleosome

1b7t Myosin 1atn Actin

1tub Microtubule1bkv Collagen

© David Goodsell

scale reduced


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HIV-1 and a Human T-cell

gp120

CD4

CCR5

HIV-1envelope

glycoprotein

T-cellsurfaceslide: Natasha Wood, Cape Town


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HIV-1 and a Human T-cell

IMAGE:http://www.sciencemag.org/content/320/5877/760/F3.large.jpg

V3 loop

slide: Natasha Wood, Cape Town


01: 04/25 Tue: no lecture02: 04/27 Thu: no lecture03: 05/02 Tue: Intro 1: organization of lecture: intro into cells & biology04: 05/04 Thu: Intro 2: amino acids, protein structure (comparison), domains05: 05/09 Tue: No lecture06: 05/11 Thu: Alignment 107: 05/16 Tue: Alignment 208: 05/18 Thu: Comparative modeling & experimental structure determination & secondary structure assignment09: 05/23 Tue: SKIP: student assembly (SVV)10: 05/25 Thu: SKIP: Ascension Day11: 05/30 Tue: SKIP: Whitsun holiday (05/15-17) 12: 06/01 Thu: 1D: Secondary structure prediction 113: 06/06 Tue: SKIP: Whitsun holiday (06/03-06)14: 06/08 Thu: 1D: Secondary structure prediction 215: 06/13 Tue: 1D: Secondary structure prediction 3 / Transmembrane structure prediction 116: 06/15 Thu: SKIP: Corpus Christi17: 06/20 Tue: 1D: Transmembrane structure prediction 2 / Solvent accessibility prediction18: 06/22 Thu: 1D: Disorder prediction19: 06/27 Tue: 2D prediction20: 06/29 Thu: 3D prediction / Nobel prize symposium21: 07/04 Tue: TBA22: 07/06 Thu: recap 123: 07/11 Tue: recap 224: 07/12 Thu: examen25: 07/13 Tue: TBA26: 07/18 Thu: TBA27: 07/20 Tue: TBA28: 07/22 Thu: TBA29: 07/25 Thu: TBA30: 07/27 Thu: TBA

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Lecture plan (CB1 structure)

today

cb1e 20170504 intro2 structure - rostlab · 2017. 5. 4. · cb1_intro2_structure lecture: protein...

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