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Solvation effects and driving forces for protein thermodynamic and kinetic cooperativity: how adequate is native-centric topological modeling?

Abstract：

:What energetic and solvation effects underlie the remarkable two-state thermodynamics and folding/unfolding kinetics of small single-domain proteins? To address this question, we investigate the folding and unfolding of a hierarchy of continuum Langevin dynamics models of chymotrypsin inhibitor 2. We find that residue-based additive Gō-like contact energies, although native-centric, are by themselves insufficient for protein-like calorimetric two-state cooperativity. Further native biases by local conformational preferences are necessary for protein-like thermodynamics. Kinetically, however, even models with both contact and local native-centric energies do not produce simple two-state chevron plots. Thus a model protein's thermodynamic cooperativity is not sufficient for simple two-state kinetics. The models tested appear to have increasing internal friction with increasing native stability, leading to chevron rollovers that typify kinetics that are commonly referred to as non-two-state. The free energy profiles of these models are found to be sensitive to the choice of native contacts and the presumed spatial ranges of the contact interactions. Motivated by explicit-water considerations, we explore recent treatments of solvent granularity that incorporate desolvation free energy barriers into effective implicit-solvent intraprotein interactions. This additional feature reduces both folding and unfolding rates vis-à-vis that of the corresponding models without desolvation barriers, but the kinetics remain non-two-state. Taken together, our observations suggest that interaction mechanisms more intricate than simple Gō-like constructs and pairwise additive solvation-like contributions are needed to rationalize some of the most basic generic protein properties. Therefore, as experimental constraints on protein chain models, requiring a consistent account of protein-like thermodynamic and kinetic cooperativity can be more stringent and productive for some applications than simply requiring a model heteropolymer to fold to a target structure.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Kaya H,Chan HS

doi

10.1016/s0022-2836(02)01434-1

keywords:

subject

Has Abstract

pub_date

2003-02-21 00:00:00

pages

911-31

issue

eissn

0022-2836

issn

1089-8638

pii

S0022283602014341

journal_volume

326

pub_type

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Solvation effects and driving forces for protein thermodynamic and kinetic cooperativity: how adequate is native-centric topological modeling?