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How do proteins fold?
Gary Benz and Claudia Winkler
What is a protein?
•Polymer (“necklace”) of amino acids
•20 types of amino acids
What do proteins do?
• Carry out molecular
function
– Antibodies, enzymes,
signals, etc
– Proteins = Nature’s
“nanomachines”
• How is this possible?
– By “folding” into a
particular shape
– Folding is fast
(milliseconds) and reliable
From necklace to protein:
Hydrogen bonds are the glue
• Two key models of
hydrogen bonding: alpha
helix and beta sheets
• (A) is example of an alpha
helix. The hydrogen bonds
(dotted lines) are between
oxygen atoms (red) and
hydrogen atoms (white)
(shown in this case as
occurring every fourth pair
of amino acids along the
protein).
• (B) shows examples of
beta-sheets held together
by hydrogen bonds.
• When the protein folds onto
itself completely it is said to
make a “hairpin”
Protein folding mechanisms
• The next few slides show four different
protein folding mechanisms currently
being studied.
• These mechanisms describe different
possible sequences and paths, shown
with arrows, that the chains of amino
acids can follow to go from the unfolded
state to the final protein form, called
the native state.
Diffusion/Collision
First form secondary
structure by
diffusion/collision)
– Hierarchical: form
helices & hairpins,
decrease entropy
unfolded state
formation of
microdomains
diffusion and collision of
microdomains
native state
Nucleation
Nucleation
– Form nucleus of
structure, then grow
(ala 1st order phase
trans)
unfolded state
formation of
a nucleus
native state
Collapse
Collapse first
– Hydrophobically
unfolded state
driven: remove water
to form hydrogen
bonds
collapse
native state
Topomer search
Form rough native
shape first (topomer
search)
– Find the right
“topology” first, then
pack side chains
unfolded state
"topomer"
native state
Evolution will use any
mechanism that works!
• No single mechanism is observed,
different examples appear in
nature
– Form secondary structure first (BBA5)
• Hierarchical: form alpha-helices & betasheets
– Collapse first (protein G Hairpin)
• Hydrophobically driven: remove water
to form hydrogen bonds first
– Form rough native shape first (Villin)
A folding simulation
Unfolding simulation