Lecture 11: Forces and Structures Flashcards
What is approximated by the Lennard-Jones potential?
distance dependence of van der Waals forces
What is the principle “glue” that holds proteins together?
hydrophobic effect
Which amino acid is the most hydrophilic? Which is most hydrophobic?
Ala - hydrophilic
Leu - hydrophobic
What is the origin of the hydrophobic effect?
water forms calthrates in a hydrophobic environment
energetically unfavorable, but best
Why is the formation of clathrates ultimately favorable?
reduces area of water exposed to hydrophobic environment
What are protein secondary structures?
alpha helix
beta sheet
beta turn
____ degrees of rotation around the _____ bond will remove carbonyl-side chain clash
60 degrees
phi
What is the rise (z-axis) of an alpha helix? How many resides per turn? This makes every ____ amino acid close in space
1.5 angstrum
3.6 residues/turn
4th
How do backbone-backbone interactions stabilize alpha helices?
NH and CO H-bonds (4 residues apart, along helix axis)
What forms the macrodipole in backbone-side chain interactions of alpha helices?
excess +/- charge on N- and C- termini, respectively
What feature in an alpha helix allows side chain-side chain interactions to occur?
3.6 residue repeat
what residues are strong helix breakers and why?
Pro - no NH –> can’t H-bond
Gly- flexible
What residue is a helix former and why?
Ala - lacks side chain, loses no rotational freedom
what residues are medium helix breakers and why?
Val, Thr, Trp, Phe
beta-branched or bulky - lose rotational freedom in helix
what residues are helix indifferent and why?
Arg, Lys, Glu
long straight chains
don’t lose as much rotational freedom
How can you tell if a peptide membrane-bound?
hydrophobic region corresponding to 6-7 turns of a helix
What is an example of an amphipathic helix?
Myoglobin
Why are parallel beta sheets less frequently observed than are antiparallel sheets?
H-bonds are slightly bent in parallel sheets
What holds alpha helcices and beta sheets together?
H-bonds
Are beta sheets flat?
No - pleated
What type of beta structure forms between adjacent strands in denaturing conditions?
Amyloid
What is the psi-phi angle of a beta sheet?
140 degrees
What are the rise and periodicity of beta sheets?
3.5Ang
2
What residue is required for a reverse beta turn? Which is preferred?
Gly required
Pro preferred
What interactions stabilize a reverse beta turn?
H-bonds
Where are reverse beta turns found?
end of one sheet to form the next
What kind of residues usually comprise loops/random coils?
hydrophilic
What is the alpha-turn-helix?
motif - txn factor
What is the difference between a domain and a motif?
motif - small - cut out of protein –> don’t have that function
domain - large, subjective
What is the antennapedia homeodomain?
txn factor
has alpha turn helix motif
in the antennapedia homeodomain, where does the alpha turn helix bind?
major groove
What is the zinc finger?
motif - txn factor
What is the primary composition of zinc fingers?
His, Cys repeats
What does Zn2+ do in a zinc finger?
holds structure together
What is the coil coil? How is it characterized?
domain - heptad repeat
What is a heptad repeat and where is it found?
coiled coil
a,d are hydrophobic
e,g have opposite charges
how are helices of a coiled coil held together?
H-bonds and van der Waals
what is the DNA binding domain of GCN2 txn factor?
coiled coil
What is the charge on the N-terminal of the GCN2 txn factor?
Very +
How is the C-terminal of the GCN2 txn factor characterized?
heptad repeat leucine zipper
How does the GCN2 txn factor demonstrate characteristics of an intrinsically disordered protein domain?
N-terminus is only structured as a helix when it is bound to DNA
(folds only when it binds its target ligand)
What are four roles of coiled coil domains?
*bind DNA
protein-protein recognition
mechanical force transduction (ex. myosin tails)
viral penetration
What designates a coiled coil?
at least 3-4 heptad repeats –> hydrophobic region
what domain differentiates flu strains?
influenza haemagglutinin
What allows fusion of the influenza virus to the host cell membrane, resulting in release of viral mRNA into the cell and infection?
fusogenic peptide - very hydrophobic
How does the flu virus enter a host cell?
endocytosis
what is the structure of the influenza haemagglutinin?
triple stranded coiled coil
Many viruses use a _______ method to gain entry to cells
harpooning
In viral entry of the flu and HIV, the mechanism of action involves ________ mediated by the _______
membrane distortion
harpooning protein
What step in viral entry of the flu and HIV have been targeted by small molecule inhibitors?
entry to host cell
What is a key difference between trigger mechanisms during harpooning in flu vs HIV?
flu induced pH change within cell
HIV induces receptor binding
What are the roles of gp120 and gp41 in HIV?
gp120 binds CD4 and CXCR4/CCR5 co-receptors; induces conformational chance in gp41
gp41 has fusogenic peptide
What happens after HIV’s fusogenic peptide is trust into cell?
form prehairpin intermediate
N-trimer and C-peptide region of gp41 come together to form six-helix bundle
What structure of HIV is vulnerable to inhibition and why?
prehairpin intermediate - long lifetime
What is the problem with targeting the HIV prehairpin intermediate? What is an example of a drug which is not successful?
drugs often degraded by protease
Fuzeon
What concept was used to create a drug which has more advantageous properties than does fuzeon?
mirror-image peptide inhibitor
D conformation binds to L conformation of gp41 tightly
