SEMINAR @ SISSA, SBP, dr. G. Colombo - April 16, at 11.00 hrs.

[Barbara Corzani]

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STATISTICAL AND BIOLOGICAL PHYSICS SEMINAR
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Dr. Giorgio Colombo
(Istituto di Chimica del Riconoscimento Molecolare, CNR, Milano)

Title:
"From Drug Design to the Dynamics and  Function  of  Biomolecules:  What  Can
Computational Biology Tell Us?"


Fri 16 April 2010 @ 11.00 a.m.

SISSA - Basement floor - room A
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Abstract:
In this study,  we  will  present  recent  results  on  the  development  of
computational biology strategies for the  discovery  of  new  inhibitors  of
protein-protein interactions with drug-like properties, and  for  the  study
of the functional dynamics and allosteric signal propagation  mechanisms  in
proteins.
       In the first part,  we  will  discuss  the  combination  of  molecular
simulations with peptide array technologies to discover  new  inhibitors  of
angiogenesis targeting  the  protein  Fibroblast  Growth  Factor-2  (FGF-2),
which may be relevant in the development of new anticancer drugs.  Based  on
the  recent  discovery  of  an  interaction  site  between  FGF-2  and   the
endogenous angiogenesis  inhibitor  thrombospondin-1  (TSP-1),  we  began  a
search for the FGF-2 binding  sequence  on  TSP-1.  Screening  of  over  200
peptides for their ability to bind  FGF-2  revealed  a  15-residue  sequence
referred to  as  DD15.  Molecular  dynamics  simulations  were  employed  to
identify the key components of the DD15-FGF-2 interaction. This  information
was validated by and NMR spectroscopy and translated  into  a  pharmacophore
that was be used to screen 290,000 compounds in  silico.  Of  258  compounds
identified in the virtual screen, 19  were  tested  experimentally,  and  of
these 3 were found  to  competitively  inhibit  the  interaction.  The  most
active compound  inhibited  angiogenesis  induced  by  FGF-2  in  vivo.  The
promising angiogenesis inhibitors discovered in  this  study  highlight  the
potential of this multidisciplinary approach  for  the  discovery  of  novel
antiangiogenic drugs.
       In the second part, we present  a  computational  analysis  of  signal
propagation  mechanisms  and  long-range  communication  pathways   in   the
molecular chaperone Hsp90. The  analysis  is  carried  out  using  molecular
dynamics (MD) simulations of the  full-length  Hsp90  dimer,  combined  with
essential dynamics, correlated motions analysis  and  a  signal  propagation
model. All-atom MD simulations with the  time  scales  of  100ns  have  been
independently carried out for Yeast Hsp90  in  complexes  with  the  natural
substrates ATP and ADP and  for  the  unliganded  dimer.  We  elucidate  the
mechanisms of signal propagation and determine hot spot  residues   involved
in the inter-domain communication pathways from the nucleotide-binding  site
to the C-terminal domain interface.  Interestingly  different  communication
mechanisms are triggered by different  ligands.  This  information  is  then
used to select for new allosteric  inhibitors  of  the  chaperone.  The  new
molecules  show  the  ability  to  allosterically  inhibit  the  chaperoneʼs
functional motions.