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

In the framework of a lattice-model study of protein folding, we investigat e the interplay between designability, thermodynamic stability, and kinetic s. To be "protein-like," heteropolymers must be thermodynamically stable, s table against mutating the amino-acid sequence, and must be fast folders. W e find two criteria which, together, guarantee that a sequence will be "pro tein like:" (i) the ground state is a highly designable structure, i.e., th e native structure is the ground state of it large number of sequences, and (ii) the sequence as a large Delta/Gamma ratio, Delta being the average en ergy separation between the ground slate and the excited compact conformati ons, and Gamma the dispersion in energy of excited compact conformations. T hese two criteria are not incompatible since, on average, sequences whose g round states are highly designable structures have large Delta/Gamma values . These two criteria require knowledge only of the compact-state spectrum. These claims are substantiated by the study of 45 sequences, with Various v alues of Delta/Gamma and various degrees of designability, by means of a Bo rst-Kalos-Lebowitz algorithm, and the Ferrenberg-Swendsen histogram optimiz ation method. Finally, we report on the reasons for slow folding. A compari son between a very slow folding sequence, an average folding one, and a fas t folding one, suggests that slow folding originates from a proliferation o f nearly compact low-energy conformations, not present for fast folders. (C ) 1999 American Institute of Physics. [S0021-9606(99)53301-1].