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Structural origin of slow diffusion in protein folding.

ABSTRACT: Experimental, theoretical, and computational studies of small proteins suggest that interresidue contacts not present in the folded structure play little or no role in the self-assembly mechanism. Non-native contacts can, however, influence folding kinetics by introducing additional local minima that slow diffusion over the global free-energy barrier between folded and unfolded states. Here, we combine single-molecule fluorescence with all-atom molecular dynamics simulations to discover the structural origin for the slow diffusion that markedly decreases the folding rate for a designed ?-helical protein. Our experimental determination of transition path times and our analysis of the simulations point to non-native salt bridges between helices as the source, which provides a quantitative glimpse of how specific intramolecular interactions influence protein folding rates by altering dynamics and not activation free energies.

SUBMITTER: Chung HS

PROVIDER: S-EPMC6260792 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Structural origin of slow diffusion in protein folding.

Chung Hoi Sung HS Piana-Agostinetti Stefano S Shaw David E DE Eaton William A WA

Science (New York, N.Y.) 20150901 6255

Experimental, theoretical, and computational studies of small proteins suggest that interresidue contacts not present in the folded structure play little or no role in the self-assembly mechanism. Non-native contacts can, however, influence folding kinetics by introducing additional local minima that slow diffusion over the global free-energy barrier between folded and unfolded states. Here, we combine single-molecule fluorescence with all-atom molecular dynamics simulations to discover the stru ...[more]

PMID: 26404828

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