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  • Title: The unfolded ensemble and folding mechanism of the C-terminal GB1 beta-hairpin.
    Author: Bonomi M, Branduardi D, Gervasio FL, Parrinello M.
    Journal: J Am Chem Soc; 2008 Oct 22; 130(42):13938-44. PubMed ID: 18811160.
    Abstract:
    In this work, we shed new light on a much-studied case of beta-hairpin folding by means of advanced molecular dynamics simulations. A fully atomistic description of the protein and the solvent molecule is used, together with metadynamics, to accelerate the sampling and estimate free-energy landscapes. This is achieved using the path collective variables approach, which provides an adaptive description of the mechanism under study. We discover that the folding mechanism is a multiscale process where the turn region conformation leads to two different energy pathways that are connected by elongated structures. The former displays a stable 2:4 native-like structure in which an optimal hydrophobic packing and hydrogen bond pattern leads to 8 kcal/mol of stabilization. The latter shows a less-structured 3:5 beta-sheet, where hydrogen bonds and hydrophobic packing provide only 2.5 kcal/mol of stability. This perspective is fully consistent with experimental evidence that shows this to be a prototypical two-state folder, while it redefines the nature of the unfolded state.
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