Correlation of early orientational ordering of engineered λ6-85 structure with kinetics and thermodynamics

Edgar Larios, Jed W. Pitera, William C. Swope, Martin Gruebele

Research output: Contribution to journalArticlepeer-review


Experimental and computational Φ-value analysis of two-state helical proteins has shown that definite interactions among helix-forming segments build up in the transition state ensemble, but this type of analysis is not applicable to downhill folders. Here, we ask whether orientational ordering of helix-forming segments occurs early on during folding of a downhill λ6-85 mutant, and how much it correlates with the thermodynamics and kinetics of various λ6-85 mutants that do have folding barriers. From a grand total of 5 μs of implicit solvent replica-exchange molecular dynamics, we conclude that under folding conditions segments 1 and 4 form more helical structure and orient correctly relative to the native structure more often than do segments 2 and 3. Helices 1 and 2 retain the most residual structure and orientation at high temperatures. This is further supported by experimental data showing that perturbations in helices 1 and 4 of this well-designed folder affect folding kinetics and stability more sensitively than elsewhere in the protein, and that the helix 1-2 only bundle retains a cooperative melting transition and helical CD spectrum. The correct orientational propensity of helices 1 and 4 at low temperature is in agreement with the work by Takada, Portman and Wolynes proposing initial structure formation during folding in helices 1 and 4 of the wild-type λ6-85 protein, a two-state folder. Thus, the absence of a large barrier in the downhill mutant does not fundamentally alter the steps the wild-type protein takes to fold.

Original languageEnglish (US)
Pages (from-to)45-53
Number of pages9
JournalChemical Physics
Issue number1
StatePublished - Mar 31 2006


  • Energy landscape
  • Helix bundle
  • Molecular dynamics
  • Thermal unfolding

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Physical and Theoretical Chemistry

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