HOW DOES A PROTEIN FOLD

THE number of all possible conformations of a polypeptide chain is too large to be sampled exhaustively. Nevertheless, protein sequences do fold into unique native states in seconds (the Levinthal paradox). To determine how the Levinthal parades is resolved, we use a lattice Mont e Carlo model in which the global minimum (native state) is known. The necessary and sufficient condition for folding in this model is that the native state be a pronounced global minimum on the potential surfa ce. This guarantees thermodynamic stability of the native state at a t emperature where the chain does not get trapped in local minima. Foldi ng starts by a rapid collapse from a random-coil state to a random sem i-compact globule. It then proceeds by a slow, rate-determining search through the semicompact states to find a transition state from which the chain folds rapidly to the native state. The elements of the foldi ng mechanism that lead to the resolution of the Levinthal parades are the reduced number of conformations that need to be searched in the se micompact globule (similar to 10(10) versus similar to 10(16) for the random coil) and the existence of many (similar to 10(3)) transition s tates. The results have evolutionary implications and suggest principl es for the folding of real proteins.