Designability, thermodynamic stability, and dynamics in protein folding: a lattice model study

In the framework of a lattice-model study of protein folding, we investigate the interplay between designability, thermodynamic stability, and kinetics. To be ‘‘protein-like,’’ heteropolymers must be thermodynamically stable, stable against mutating the amino-acid sequence, and must be fast folders. We find two criteria which, together, guarantee that a sequence will be ‘‘protein like:’’ ~i! the ground state is a highly designable structure, i.e., the native structure is the ground state of a large number of sequences, and ~ii! the sequence has a large D/G ratio, D being the average energy separation between the ground state and the excited compact conformations, and G the dispersion in energy of excited compact conformations. These two criteria are not incompatible since, on average, sequences whose ground states are highly designable structures have large D/G values. These two criteria require knowledge only of the compact-state spectrum. These claims are substantiated by the study of 45 sequences, with various values of D/G and various degrees of designability, by means of a Borst–Kalos–Lebowitz algorithm, and the Ferrenberg–Swendsen histogram optimization method. Finally, we report on the reasons for slow folding. A comparison between a very slow folding sequence, an average folding one, and a fast folding one, suggests that slow folding originates from a proliferation of nearly compact low-energy conformations, not present for fast folders. © 1999 American Institute of Physics. @S0021-9606~99!53301-1#