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Kinetics and thermodynamics of folding of a de novo designed four-helix bundle protein.

Abstract：

:A simple continuum model of a de novo designed model of a four-helix bundle is presented. The thermodynamics and kinetics of the model are studied using Langevin simulations. We use a three-letter minimal off-lattice representation of a de novo designed four-helix bundle protein. The native state of the model, which can be thought of as an alpha-carbon representation of the peptide chain, is a caricature of the sequence designed by Ho and Degrado and shows several characteristics found in the naturally occurring four-helix bundles. These include the structural aspects and the relative stability of the native conformation. The model four-helix bundle shows two characteristic temperatures T theta and Tf. The former is the temperature above which the structure resembles that of the random coil. Below the first-order folding transition temperature Tf the chain adopts the native conformation corresponding to the four-helix bundle. It is shown that in order to obtain a unique native structure a proper free energy balance between secondary and tertiary interactions is needed. The thermal denaturation starting from the unique native conformation indicates that at least a three-state analysis is required. The intermediates in the equilibrium thermal denaturation are all found to be native-like. The kinetics of refolding starting from an ensemble of denatured states shows that the acquisition of the native conformation takes place via a kinetic partitioning mechanism. A fraction of molecules, phi, reaches the native state by a topology inducing nucleation collapse mechanism, while the remainder (1-phi) follows a complex three-stage multipathway process. We suggest, in accord with our earlier studies, that phi is essentially determined by the intrinsic temperature scales T theta and Tf. Our studies indicate that better design of proteins can be achieved by making T theta as close to Tf as possible. Experimental implications for de novo design of proteins are briefly discussed.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Guo Z,Thirumalai D

doi

10.1006/jmbi.1996.0578

subject

Has Abstract

pub_date

1996-10-25 00:00:00

pages

323-43

issue

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(96)90578-1

journal_volume

263

pub_type

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Kinetics and thermodynamics of folding of a de novo designed four-helix bundle protein.