STRUTTURA DELLE PROTEINE,
UN CAMPO DI RICERCA
VERAMENTE INTERDISCIPLINARE
Andrea Bernini
Structural Biology Lab – www.sbl.unisi.it
[email protected]
18/03/2014@Dipartimento Ingegneria dell’Informazione e Scienze Matematiche
USING SIGHT TO EXPLOIT
MOLECULAR KNOWLEDGE
Andrea Bernini
Structural Biology Lab – www.sbl.unisi.it
[email protected]
18/03/2014@Dipartimento Ingegneria dell’Informazione e Scienze Matematiche
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Structural biology is a branch of molecular biology, biochemistry,
and biophysics concerned with the molecular three-dimensional structure
of biological macromolecules such as proteins, RNA, and DNA.
Structural bioinformatics is the branch of bioinformatics which is
related to the analysis and prediction of the structure of biological
macromolecules. It deals with generalizations about macromolecular 3D
structure such as comparisons of overall folds and local motifs, principles
of molecular folding, evolution, and binding interactions, and
structure/function relationships, working both from experimentally solved
structures and from computational models. Structural bioinformatics can
be seen as a part of computational structural biology.
NASCE LA BIOLOGIA STRUTTURALE
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1958: John Kendrew determina la struttura tridimensionale della
mioglobina e ne fa un modello in plastilina.
Oggi: la stessa molecola di
mioglobina visualizzata in
grafica 3D con un software
gratuito
STRUCTURAL LEVELS OF PROTEINS
PROTEIN FOLDING AND ENERGY
LANDSCAPE
SIR KENDREW AND MYOGLOBIN, 1958
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This plasticine model of myoglobin,
made by Sir John Kendrew, was the
first ever model to be made of a
protein molecule. In 1958 John
Kendrew (1917-1977) and Max Perutz
(1914-2002) were able to produce a
model of its 3-dimensional structure,
for which they were awarded the
Nobel Prize for chemistry in 1962.
The contorted cylindrical shape,
showing the track of polypeptide
chain, is supported by wooden rods
protruding from a pegboard base;
dimensions of base 18" x 1 1/2"; overall
height 8 1/2". The forest of rods
obscured the view of the model and
made it hard to adjust. Its size made it
cumbersome and problematic to move.
1965: Kendrew commissiona
ad A. A. Barker i primi modelli
della mioglobina in palline di
metacrilato (e li vende a
600$, stimabili in 4’300$ alla
data odierna) .
FROM PHYSICAL MODELS TO
ABSTRACTION….
The domain I of CD11a (membrane
integrin), wire model decorated with
pipecleaner (late 90’s)
The same protein rendered by
computer graphics (MolMol)
EARLIEST COMPUTER REPRESENTATIONS
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As early as 1964, Cyrus Levinthal and
his colleagues at MIT had developed a
system that displayed, on an
oscilloscope, rotating "wireframe"
representations of macromolecular
structures.
In a similar way, ATARI created the
videogame Asteroids in 1979.
Videogame came later than molecular
representation but development rate
had been different…
EVANS & SUTHERLAND COMPUTERS:
1980-1990
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During the 1980's, the most popular
computer system for crystallographers
was manufactured by Evans &
Sutherland. These computers, costing
about $250,000 in 1985, displayed the
electron density map, and enabled an
amino acid sequence to be fitted
manually into the map.
MOLECULAR GRAPHICS FOR THE MASSES:
ROGER SAYLE'S RASMOL, 1993
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In 1990, Roger entered graduate
school in computer science at the
University of Edinburgh. Roger
developed his program into a more
molecular visualization system, and
by 1993, it was being used in
teaching and for images in research
publications. Roger generously
made the program available to the
world scientific community free of
charge when he received his Ph.D.
in June, 1993. In January, 1994,
Roger was employed by
GlaxoWellcome, which supported
the continued development of
RasMol freeware, including the first
version for the Macintosh, for the
next two years.
www.openrasmol.org
JMOL, THE MOLECULAR VIEWER OF THE
INTERNET AGE
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Jmol is a free, open
source molecule
viewer in the form of a
Java applet. It is
cross-platform,
running on Windows,
Mac OS X, and
Linux/Unix systems.
jmol.sourceforge.net
SOURCES OF MOLECULAR STRUCTURES
Protein Data Bank (www.rcsb.org) – macromolecules
e.g. 2O7N
 PubChem (pubchem.ncbi.nlm.nih.gov) – small molecules
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STRUCTURE OF DENGUE VIRUS
Dimer of glycoprotein-E
Icosahedral scaffold of 90 glycoprotein-E dimers
Aedes aegypti, the principal mosquito vector of dengue viruses (right)
Another important mosquito vector of dengue is Aedes albopictus (tiger, left)
L’IMPORTANZA DELLA FORMA DELLE MOLECOLE:
L’INFLUENZA AVIARIA E LO ZANAMIVIR
zanamivir (yellow) oseltamivir (green) sialic acid (gray)
L’IMPORTANZA DELLA FORMA DELLE MOLECOLE:
L’INFLUENZA AVIARIA E LO ZANAMIVIR
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L’influenza aviaria è di tipo H5N1 (Hemagglutinin 5 e
Neuraminidase 1)
N1 NEUROAMINIDASE, 3CKZ
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Structure determined in 2008 by
X-ray cristallography
Neuraminidases catalyze the
hydrolysis of terminal sialic acid
residues from the newly formed
virions and from the host cell
receptors. Neuraminidases
activities include assistance in
the mobility of virus particles
through the respiratory tract
mucus and in the elution of virion
progeny from the infected cell.
MODELING OF SARS CORONAVIRUS SPIKE PROTEIN
ANALYSIS OF PROTEIN STRUCTURE
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SADIC: Simple Atom Depth Index Calculator
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ProCoCoA: Protein Core Composition Analyzer