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π- Stacking Interaction
Ana Gabriela Murguía
Carlos Villa
π- Stacking Interaction
• Proteínas no homologas
• Difracción de Rayos X
• Posición preferida y orientación de
interacciones no covalentes
• Aminoácidos Aromáticos (Cad. Laterales)
• Dimeros
π- Stacking Interaction
• Agentes medicinales contienen
sustituyentes aromáticos
• El reconocimiento diferencial esta basado
en las interacciones aromáticas
Estructuras
T-Shaped
(1t)
Off centered parallel displaced
(1p)
Hipótesis
• En el core de la proteína (Hidrofobico) en
el estado sólido, las propiedades
dinámicas de la interacción bencenobenceno están satisfechas y una
estructura preferida prevalece,
aunque……………………………
Dímero de Benceno
Materiales y Métodos
Determinación del Centroide
Distancia más cercana de contacto
Esta combinación de datos corresponde a
“Off centered parallel configuration”
La forma de la distribución Y puede
ser extrapolada a una distribución de
Boltzman, bajo ciertas asunciones
Resultados
• La estructura paralela descolocada es
mas estable que la estructura con forma T
• La diferencia de la energia es dependiente
del seno y
• La tempertura es 300K
Discusión
• La estructura paralela descolocada es
mas estable que una estructura de forma
T en 0.5 – 0.75 kcal/mol
• Phe-Phe en 1.0 kcal/mol
• Otros autores dicen lo contrario (además
que no existen en proteínas) Quizás
debido a descuido en la distribución de los
ángulos
Aromatic Interaction
• π-π interaction is a noncovalent interaction
between organic compounds containing aromatic
moieties.
• π-π interactions are caused by intermolecular
overlapping of p-orbitals in π-conjugated systems,
so they become stronger as the number of πelectrons increases.
The role of -stacking in self-assembly
processes
• Many areas of chemistry and biochemistry,
most notably in molecular recognition and
self-assembly.
• Aromatic rings tend to form high-order
clusters of four different types: parallel
displaced, Tshaped,parallel staggered, or
Herringbone.
Amyloid formation
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Alzheimer’s disease (AD)
Diabetes mellitus (type II)
Prion diseases
Familial amyloidosis
Light chain amyloidosis
Formation is a process in which normal wellfolded cellular proteins undergo a self-assembly
process that leads to the formation of large and
ordered protein structures.
Aromatic residues in short amyloid
related peptide
Islet amyloid polypeptide
• Minimal amyloid-forming fragment of the 37 amino
acid islet amyloid polypeptide (IAPP), or amylin.
• IAPP deposits found postmortem in 95% diabetes.
• Peptide form amyloid fibers in vitro.
• 6 residue peptide fragment of human IAPP
(NFGAIL) form amyloid fibrils similar to the fulllength protein.
• 5 residue fragment (FGAIL) forms ordered
amyloid fibrils, are different in morphology from
the full-length peptide.
• A shorter peptide corresponding to the GAIL
sequence did not form any fibrils at all.
Alzheimer’s -amyloid
• Brain senile amyloid plaques composed of the AB
peptide
• Short fragment of AB contains 2 phenylalanine
residues (QKLVFF) was shown to bind specifically to
full-length peptide.
• The short peptide could inhibit amyloid formation by
the full-length AB polypeptide.
• LVFFA and its derivatives and LPFFD
• KLVFFAE, forms amyloid fibrils.
• Amyloid fibrils process of Molecular recognition and
self-assembly, the high affinity and selectivity of the
FF motif seems to provide the molecular recognition.
Aortic medial amyloid
• Aromatic residues is the octapeptide fragment
(NFGSVQFV) of the 364 amino acid lactadherin
protein.
• Amino acid sequence analysis of the 5.5 kDa
peptide demonstrated that derived from an integral
proteolytic fragment of lactadherin.
• Was synthesized and characterized form amyloid
deposits
Animal and yeast prions
• Animal prion diseases are sporadic or inherited
neurodegenerative disorders that are transmitted by a protein
infective agent.
• The agent is a misfolded form (PrS) of a normal cell protein
(PrP) that acts by a conversion of normal folded PrP proteins
to amyloid-like aggregates.
• The importance of the octapeptide repeats is the fact result
from the insertion of one to nine extra octapeptide repeats in
addition to the five repeats that occur in the normal prion
protein.
• A misfolded variant in yeast (Sup35p) of a normal cellular
protein (Sup35), which has been shown to cause a change in
the phenotype of a normal cell by converting the normal
protein into aggregates.
The role of -stacking interactions in
chemistry
• Amyloid fibril formation is basically a process of
intermolecular recognition and self-assembly, the
-stacking can provide:
• 1) an energetic contribution that stems from the
stacking itself; such a contribution can
thermodynamically drive the self-assembly
process,
• 2) specific directionality and orientation provided
by the specific pattern of stacking.
Cont …
• The mechanism of amyloid includes a stepwise
assembly of short recognition elements.
• At the first stage, 2 structural elements that
contain aromatic residues form a bimolecular
structure, which is restricted by the allowed
geometry of - stacking.
• Followed by a stepwise addition of further
monomers containing the same recognition
elements.
• Again, the overall structural organization of the
addition process is being directed by the
restricted geometries of the stacking interaction.