The folding mechanism of larger model proteins: role of native structure.

Abstract

The folding mechanism of a 125-bead heteropolymer model for proteins is investigated with Monte Carlo simulations on a cubic lattice. Sequences that do and do not fold in a reasonable time are compared. The overall folding behavior is found to be more complex than that of models for smaller proteins. Folding begins with a rapid collapse followed by a slow search through the semi-compact globule for a sequence-dependent stable core with about 30 METHODSWe generated a data base of 200 sequences, tested each for its ability to fold, and looked for sequence attributes that have a high correlation with rapid folding. Such an approach requires that the sequences that make up the data base have a range of folding abilities. The probability of finding random sequences that satisfy both the thermodynamic and kinetic requirements for folding is very small for a 125-mer. Unlike the 27-mer case, where 54 out of 200 sequences were found to fold (2), none was found in ten 125-mer sequences. If the fraction of sequences satisfying the thermodynamic requirement is large (-1%) and independent of chain length, as proposed by Shakhnovich and Gutin (7), this suggests that the stability criterion is not sufficient for satisfying the kinetic requirement for folding in the 125-mer. Consequently, to obtain a 125-mer data base with a significant fraction of folding sequences, nonrandom properties must be introduced. To examine the possible role of secondary structure (see Table 1 and ref. 8), we designed sequences with substantial amounts of helices and sheets. From an ensemble of fully compact 5 x 5 x 5 (176-contact) conformations, we selected 100 otherwise random structures with a large fraction (between 40 and 100%) of contacts in sheets and 100 otherwise random structures with a large fraction (between 34 and 54%) of contacts in helices. Each of the 200 chosen structures serves as the starting point for a design process that creates a sequence for which that structure is the native (lowest energy) state. The resulting sequences can be regarded -as representing, respectively, the (3-sheet and a-helical classes of proteins (9).The energy function used here has the same form as that employed previously (2,5). It is the sum over all contacts: E = Y.i<j A(ri -rj)(Bij + Bo). The function A(ri -rj) selects the interacting monomer pairs; it is unity if i andj, located at ri and rj, respectively, are in contact and zero otherwise. Bij gives the specific interaction energy between monomers i andj; a complete set of Bij defines a sequence. The quantity Bo (Bo < 0) is a Abbreviations: MC, Monte Carlo; Tm, melting temperature. 8356The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Hydrophobic forces and the length limit of foldable protein domains

“…Consistent with the "thousands to millions" of degenerate optimal conformations estimated from explicit enumeration, hN HP i ≈ 10 4 for L ¼ 48. At a higher level of chemical accuracy, for a L ¼ 80 lattice chain consisting of the 20 types of amino acids and with a unique native fold, it was found that at most 10 6 Monte Carlo steps were required to reach the native fold (22). This is in agreement with Eq.…”

The folding process of hen lysozyme: a perspective from the ‘new view’

“…Recent 'dead-time' labelling experiments [23] reveal the formation of an embryonic native-like structure in the h-domain at this very early stage of folding which, although only marginally stable, is probably significant in laying the foundations for the later stages of folding. Interestingly, such secondary structure with native-like character has been shown to speed up the search in the collapsed state for the nativelike folding 'core' in simulations of the folding of a 125-mer protein [24]. The hydrophobically collapsed state which is formed at the onset of the folding process of lysozyme has been suggested to have properties characteristic of equilibrium molten globule states [14,[17][18][19][20][21]23].…”

Effect of local thermal fluctuations on folding kinetics: A study from the perspective of nonextensive statistical mechanics

“…Indeed, sequences are usually generated and tested for its ability to fold rapidly in an small and specific range of temperature [39], even knowing that this procedure eliminates many suitable structures that would otherwise be important for kinetic studies. But a new perspective emerges when local thermal fluctuations experienced by nanoscale structures is associated with its spatial characteristics (as its size and degrees of freedom), by means of the parameter q from the nonextensive statistical mechanics.…”