期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 326, 期 3, 页码 911-931出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/S0022-2836(02)01434-1
关键词
calorimetric cooperativity; single-exponential kinetics; unfolding; chevron plot; desolvation barrier
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 G (o) over bar -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-A-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 Go-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. (C) 2003 Elsevier Science Ltd. All rights reserved.
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