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

摘要

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 #DELTA#/#GAMMA# ratio, #DELTA# being the average energy separation between the ground state and the excited compact conformations, and #GAMMA# the dispersion in energy of excited compact conformation. These two criteria are not incompatible since, on average, sequences whose ground 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 values of #DELTA#/#GAMMA# 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.