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Research Article

Protein folding funnels: a kinetic approach to the sequence-structure relationship.

P E Leopold, M Montal, and J N Onuchic
PNAS September 15, 1992 89 (18) 8721-8725; https://doi.org/10.1073/pnas.89.18.8721
P E Leopold
Department of Physics, University of California, San Diego, La Jolla 92093-0319.
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M Montal
Department of Physics, University of California, San Diego, La Jolla 92093-0319.
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J N Onuchic
Department of Physics, University of California, San Diego, La Jolla 92093-0319.
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Abstract

A lattice model of protein folding is developed to distinguish between amino acid sequences that do and do not fold into unique conformations. Although Monte Carlo simulations provide insights into the long-time processes involved in protein folding, these simulations cannot systematically chart the conformational energy surface that enables folding. By assuming that protein folding occurs after chain collapse, a kinetic map of important pathways on this surface is constructed through the use of an analytical theory of probability flow. Convergent kinetic pathways, or "folding funnels," guide folding to a unique, stable, native conformation. Solution of the probability flow equations is facilitated by limiting treatment to diffusion between geometrically similar collapsed conformers. Similarity is measured in terms of a reconfigurational distance. Two specific amino acid sequences are deemed foldable and nonfoldable because one gives rise to a single, large folding funnel leading to a native conformation and the other has multiple pathways leading to several stable conformers. Monte Carlo simulations demonstrate that folding funnel calculations accurately predict the fact of and the pathways involved in folding-specific sequences. The existence of folding funnels for specific sequences suggests that geometrically related families of stable, collapsed conformers fulfill kinetic and thermodynamic requirements of protein folding.

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Protein folding funnels: a kinetic approach to the sequence-structure relationship.
P E Leopold, M Montal, J N Onuchic
Proceedings of the National Academy of Sciences Sep 1992, 89 (18) 8721-8725; DOI: 10.1073/pnas.89.18.8721

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Protein folding funnels: a kinetic approach to the sequence-structure relationship.
P E Leopold, M Montal, J N Onuchic
Proceedings of the National Academy of Sciences Sep 1992, 89 (18) 8721-8725; DOI: 10.1073/pnas.89.18.8721
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