Structural origin of slow diffusion in protein folding

• Autores: Hoi Sung Chung, Stefano Piana, David E. Shaw
• Localización: Science, ISSN 0036-8075, Vol. 349, Nº 6255, 2015, págs. 1504-1510
• Idioma: inglés
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• Resumen

  • 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 α-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.