Finding the Fold

The Fold Arrives in Milliseconds

• A chain of amino acids must reach one specific three-dimensional fold to function, and the same sequence gives the same fold every time.
• Levinthal's arithmetic: a 100-residue chain with 3 states per residue has 3¹⁰⁰, about 5 x 10⁴⁷ conformations. At 10^-13 seconds per conformation, a random search takes about 1.6 x 10²⁷ years. Real folding takes milliseconds. The gap between these figures is Levinthal's Paradox.
• Levinthal's own 1969 estimate was about 10³⁰⁰ configurations for a 150-residue protein. He proposed that folding is speeded and guided by the rapid formation of local interactions (Levinthal 1969).
• The energy landscape funnel, developed by Onuchic, Wolynes, and colleagues in the 1990s, explains the efficiency: the native state sits at the bottom of a funnel and the protein rolls downhill. The page adds that the funnel is a property of the amino acid sequence.
• Chaperones (Hsp70, GroEL/GroES) help about 30% of proteins reach their native state. The GroEL cage encloses a client protein and uses ATP to give it another chance to fold. The animation page gives seven ATP per folding cycle.
• Douglas Axe (2004) estimated functional enzyme folds at roughly 1 in 10⁷⁷ of sequences for a domain-sized protein.

A 100-residue chain has about 5 x 10⁴⁷ possible conformations, and the sequence carries the folding instructions that lead it to the right one in milliseconds.