The Limited Role of Nonnative Contacts in the Folding Pathways of a Lattice Protein

JOURNAL OF MOLECULAR BIOLOGY

卷:392

Article

Gin, Brian C.^1,2,3  Garrahan, Juan P.⁴  Geissler, Phillip L.^1,2 

[1] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA

[2] Univ Calif Berkeley, Lawrence Berkeley Lab, Chem Sci & Phys Biosci Div, Berkeley, CA 94720 USA

[3] Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA

[4] Univ Nottingham, Sch Phys & Astron, Nottingham NG7 2RD, England

关键词: Go model;    nonnative contacts;    lattice model;    protein folding;    principle of minimum frustration;   

DOI  :  10.1016/j.jmb.2009.06.058

来源: Elsevier

【 摘 要 】

Models of protein energetics that neglect interactions between amino acids that are not adjacent in the native state, such as the Go model, encode or underlie many influential ideas on protein folding. Implicit in this simplification is a crucial assumption that has never been critically evaluated in a broad context: Detailed mechanisms of protein folding are not biased by normative contacts, typically argued to be a consequence of sequence design and/or topology. Here we present, using computer simulations of a well-studied lattice heteropolymer model, the first systematic test of this oft-assumed correspondence over the statistically significant range of hundreds of thousands of amino acid sequences that fold to the same native structure. Contrary to previous conjectures, we find a multiplicity of folding mechanisms, suggesting that Go-like models cannot be justified by considerations of topology alone. Instead, we find that the crucial factor in discriminating among topological pathways is the heterogeneity of native contact energies: The order in which native contacts accumulate is profoundly insensitive to omission of nonnative interactions, provided that native contact heterogeneity is retained. This robustness holds over a surprisingly wide range of folding rates for our designed sequences. Mirroring predictions based on the principle of minimum frustration, fast-folding sequences match their Go-like counterparts in both topological mechanism and transit times. Less optimized sequences dwell much longer in the unfolded state and/or off-pathway intermediates than do Go-like models. For dynamics that bridge unfolded and unfolded states, however, even slow folders exhibit topological mechanisms and transit times nearly identical with those of their Go-like counterparts. Our results do not imply a direct correspondence between folding trajectories of Go-like models and those of real proteins, but they do help to clarify key topological and energetic assumptions that are commonly used to justify such caricatures. (C) 2009 Elsevier Ltd. All rights reserved.

【 授权许可】

Free