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?

• How is this possible?– By “folding” into a

particular shape– Folding is fast

(milliseconds) and reliable

• Carry out molecular function– Antibodies, enzymes,

signals, etc– Proteins = Nature’s

“nanomachines”

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 ofmicrodomains

diffusion and collision ofmicrodomains

native state

Nucleation

Nucleation– Form nucleus of

structure, then grow (ala 1st order phase trans)

unfolded state

formation ofa nucleus

native state

Collapse

Collapse first– Hydrophobically driven:

remove water to form hydrogen bonds

unfolded state

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 & beta-

sheets

– 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