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Abril 2003. Predicción de estructura de proteínas. MASTER BIOINFORMÁTICA 2003. Paulino Gómez-Puertas. Centro de Astrobiología. CSIC-INTA. by: R. Guigó. ATP. subunit. Molecular chaperonin GroEL. heptamer. (Dr Jianpeng Ma, Harvard Univ.). From DNA sec. to protein. Genome sequencing.

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Abril 2003

Predicción de estructura de proteínas.

MASTER BIOINFORMÁTICA 2003.

Paulino Gómez-Puertas.

Centro de Astrobiología. CSIC-INTA



ATP

subunit

Molecular chaperonin

GroEL

heptamer

(Dr Jianpeng Ma, Harvard Univ.)



Genome sequencing.

Growth of EMBL

H. sapiens

D. melanogaster

C. elegans

S. cerevisiae

Tamaños milesORFs Mbases

Mycoplasma 0.6

Bacterias 3-4 1-4

Levadura 6 16

Humano 70-125 3200

E. coli

by D. Devos

H. influenzae


Sequence, structure and function

Function

Sequence

Structure



Actin

DnaK

Hsc70

FtsA

MreB

Hexokinase



Protein structure determination

USA

Northeast Struct. Genomics Research Consor. Rutgers U.

NY Struct. Genomics Research Rockefeller U.

Southeast Collab. Struct. Genomics U. Georgia

Struct. Genomics Center Lawrence Berkeley Natl. Lab.

Joint Center for Struct. Genomics Scripps Research Inst.

Tuberculosis Bact. Struct. Genomics Consort Los Alamos Natl. Lab.

Midwest Center for Struct. Genomics Argonne Natl. Lab.

Others

CNRS Orsay/Gif-sur-Yvette

Protein Structure Factory Berlin

NMR facility Oxford

Astex Technology Cambridge

RIKEN Tokyo

Xray crystallography

NMR

By D. Devos


EMBL

PDB


Physical principles: not in the next few years?

Informatics (copying from known cases)

- Homology modeling

Score = 85.1 bits (208), Expect = 6e-19

Identities = 27/56 (48%), Positives = 42/56 (74%), Gaps = 1/56 (1%)

Query: 2 FIAIYDYKAETEEDLTIKKGEKLEIIEKEGD-WWKAKAIGSGEIGYIPANYIAAAE 56

F+A+YDY+A TE+DL+ KGEK +I+ WW+A+++ +GE GYIP+NY+A +

Sbjct: 8 FVALYDYEARTEDDLSFHKGEKFQILNSSEGDWWEARSLTTGETGYIPSNYVAPVD 63

- Threading

MAKEFGIPAA VAGTVLNVVE AGGWVTTIV

S ILTAVGSGGL SLLAAAGRES IKAYLKKEIK

KKGKRAVIAW

Fold

ranking

PDB

Pseudo-Energy level?

By D. Devos

Protein structure prediction

MAKEFGIPAA VAGTVLNVVE

AGGWVTTIVS ILTAVGSGGL SLLAAAGRES IKAYLKKEIK

KKGKRAVIAW



[email protected]: Simulations of the villin headpiece

3 Phe

1 Trp

1 Phe

The folding time is on the order of 10 micro-seconds.

CA(2+)-REGULATED ACTIN-BINDING PROTEIN.

VILLIN CONSISTS OF A LARGE CORE FRAGMENT, THE AMINO-TERMINAL PORTION, AND A SMALL HEADPIECE, THE CARBOXYL-TERMINAL PORTION. THE HEADPIECE BINDS F-ACTIN STRONGLY IN BOTH THE PRESENCE AND ABSENCE OF CALCIUM.

MAJOR COMPONENT OFMICROVILLI OF INTESTINAL EPITHELIAL CELLS.



Physical principles: not in the next few years?

Informatics (copying from known cases)

- Homology modeling

Score = 85.1 bits (208), Expect = 6e-19

Identities = 27/56 (48%), Positives = 42/56 (74%), Gaps = 1/56 (1%)

Query: 2 FIAIYDYKAETEEDLTIKKGEKLEIIEKEGD-WWKAKAIGSGEIGYIPANYIAAAE 56

F+A+YDY+A TE+DL+ KGEK +I+ WW+A+++ +GE GYIP+NY+A +

Sbjct: 8 FVALYDYEARTEDDLSFHKGEKFQILNSSEGDWWEARSLTTGETGYIPSNYVAPVD 63

- Threading

MAKEFGIPAA VAGTVLNVVE AGGWVTTIV

S ILTAVGSGGL SLLAAAGRES IKAYLKKEIK

KKGKRAVIAW

Fold

ranking

PDB

Pseudo-Energy level?

By D. Devos

Protein structure prediction

MAKEFGIPAA VAGTVLNVVE

AGGWVTTIVS ILTAVGSGGL SLLAAAGRES IKAYLKKEIK

KKGKRAVIAW


Structure & sequence similarity

Lesk & Chothia, 1986

Sander & Schneider, 1991


Structure to function

(some examples)


a1

b1

a2

b2

a4

a3

b3

b4

b5

a5

a6

b6

b7

a7

a8

b8

Hydroxymethylglutaryl-CoA lyase


Hydroxymethylglutaryl-CoA lyase

R41

D42

a2

a1

S75

D42

L263

S75

L263

a3

E279

a8

C

a4

N

D204

S201

H233

a7

H233

a5

D204

a6

V70

C

S201

S75

E279

H233

R41

D204

D42

L263


S201

Y201

H233

D204

R75

S75

D42

Hydroxymethylglutaryl-CoA lyase

A

B


Estrogen Receptor-DNA binding. The estrogen receptor recognizes and binds specific sequences of DNA. Upon binding, the protein induces bending in the DNA axis.


High Density Lipoprotein Particle. The model surrounded a circular disk of 160 lipids, forming a bilayer, with two apoA-I proteins and 6000 water molecules,altogether a 46,000 atom system.


Kinesin Motility

Kinesin is a force-generating enzyme, or motor protein, which convertsthe free energy of the gamma phosphate bond of ATPinto mechanical work. This work is used to power the transport of intracellular organelles along microtubules.

http://www.proweb.org/~kinesin/

Liz Greene, Steve Henikoff & Sharyn Endow


Kinesin Motility

Kinesin itself is an alpha2-beta2 heterotetramer of two heavy and two light chains

How does kinesin walk along a MT protofilament?

Twisting

model

Floppy logic model

Alternate-sides model

Rob Cross & Minia Alonso

http://mc11.mcri.ac.uk/wrongtrousers.html


Kinesin Motility

Neurospora crassa kinesin

Song et al. (2001)

http://www.mpasmb-hamburg.mpg.de/ktdock/

Mandelkow lab


Kinesin Motility

Model of kinesin dimer walking along a microtubule protofilament. (Hoenger et al.2000).

http://www.mpasmb-hamburg.mpg.de/ktdock/

Mandelkow lab


Kinesin Motility

Animated Model for Processive Motility by Kinesin

Animated Model for Muscle Myosin-Based Motility

http://www.scripps.edu/milligan/projects.html

Ron Milligan Lab


Bioinformatics Lab.

Eduardo López Viñas

Ugo Bastolla

Paulino Gómez-Puertas

Centro de Astrobiología (CSIC-INTA)



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