Application of a chaperone‐based refolding method to two‐ and three‐dimensional off‐lattice protein models

Abstract

A model of protein-chaperone interaction as a two-phase (unfolding/refolding) iterative annealing mechanism able to promote structural segregation of hydrophobic and hydrophilic monomers and thereby facilitate access to nativelike states has recently been applied successfully to two 22-mers of the Honeycutt and Thirumalai BLN (hydrophobic, hydrophilic, neutral) heteropolymer model. This technique is here applied to a much wider data set: 94 8-mers of the off-lattice protein model originally presented in two dimensions by Stillinger and Head-Gordon, and later extended into three dimensions by Irbäck and Potthast; the model chaperone is shown to be equally successful, and by progressive elaboration of the chaperone model as in the earlier BLN model work, to be utilizing very similar underlying mechanisms. It is demonstrated that on average, contacts with the model chaperone give rise to a consistent movement in structure space in the direction of more nativelike structures; this method of global minimization does not therefore rely fundamentally on random search. Insofar as the responses to the chaperone of the two- and three-dimensional forms of the substrate model do differ, this can be interpreted as reflecting the different handling of hydrophilic monomers in the models-in particular, whether there is active repulsion between these and monomers of hydrophobic character. The chaperone-induced refolding method is also tested on a set of 220 9-mer chains of each version of the substrate model, where it is seen that the two-dimensional model, with its more clearly distinguished roles for the hydrophobic and hydrophilic monomers, shows a more favorable scaling behavior.

Folding behavior of chaperonin‐mediated substrate protein

“…The change of free energy landscape and related effects has been widely discussed, and the effect of confinement and interactions were of initial concern. However, the related folding of proteins in chaperonin systems is quite complicated and still attracts many researchers 18, 33–35, 41, 42. In a work by Jewett et al,18 the folding of a highly frustrated protein within the hydrophobic chaperonin cavity was shown to be accelerated if the hydrophobicity of the chaperonin environment is moderate.…”

Reduced models of proteins and their applications

“…These focused on dynamics and thermodynamics of idealized protein motifs, as single helices [243], small helical bundles [10,11,276,278,303,304], small b-sheets [240,241,277], b-barrels [197,203,305], and idealized models of real proteins [306,307]. These studies contributed significantly to our understanding of the role of various interactions in polypeptides [196,199,243,275,303], the origin of the two-state folding transition, the folding pathways and nucleation of the process [264,305], and also effects of external restraints [241,308], including models of chaperone -protein systems [309,310] on the protein folding mechanism. Possibly, such simplified models could also provide a guideline for the design of artificial proteins [276,304].…”

Offlattice model in the prediction of protein 3D structure

“…A successful prediction should be in accordance with the native structure, but it is unreachable in practice now [5] . In this work, we will try to solve the offlattice model problem in 3-demensions with a new algorithm [6] . We develop the 3-dimension HPNX offlattice model from 2-dimension HP offlattice model.…”

“…Offlattice protein models [5,6] are important in protein folding. Assuming that the folded state is thermodynamically stable [7] , the problem can be formulated as follows: for a given sequence and interactions between residues, find the conformation with minimal energy.…”