Lecture 4: Sequence & Conformation

central principle: sequence specifies conformation

→ the order of amino acids in a polypeptide chain determines the protein’s 3D shape

→ each protein normally folds into a single shape

• folding spontaneous and driven by the hydrophobic effect

→ the native state’s structure is the most thermodynamically stable

protein folding

• process of progressive stabilization in which partly correct intermediates are retained

  • have near-native conformation so slightly more stable

• side chain interactions gradually lock fluctuating polypeptide into shape

• molecular chaperones may also assist with protein folding

  • prevents proteins from aggregating into nonfunctional structures

  • many chaperones are heat shock proteins (Hsp)

exceptions to the central principle

• for some proteins, the 1st degree structure does not dictate the 3rd degree structure

• intrinsically unstructured proteins assume a structure based on interactions with other molecules

  • often contain short “chameleon sequences” that undergo dramatic changes in secondary structure

• metamorphic proteins have two (or more) native states that are of equal energy; “dual folding” proteins

  • structural rearrangement repacks interior and forms new active site

  • different native states have different functions

proteins can have different folds; same function

→ aB-barrel, or a TIM-barrel (Triosephosphateisomerase)

→ most common protein fold in all proteins

Christian Anfinsen

one globular protein, one native state

Ron Laskey

coined term “molecular chaperone”

Alexey Murzin

coined term “metamorphic protein”

Richard Kriwacki

IDed intrinsically unstructured protein p21