Observation of complete pressure-jump protein refolding in molecular dynamics simulation and experiment

Yanxin Liu, Maxim B. Prigozhin, Klaus J Schulten, Martin Gruebele

Research output: Contribution to journalArticlepeer-review


Density is an easily adjusted variable in molecular dynamics (MD) simulations. Thus, pressure-jump (P-jump)-induced protein refolding, if it could be made fast enough, would be ideally suited for comparison with MD. Although pressure denaturation perturbs secondary structure less than temperature denaturation, protein refolding after a fast P-jump is not necessarily faster than that after a temperature jump. Recent P-jump refolding experiments on the helix bundle λ-repressor have shown evidence of a <3 μs burst phase, but also of a ∼1.5 ms "slow" phase of refolding, attributed to non-native helical structure frustrating microsecond refolding. Here we show that a λ-repressor mutant is nonetheless capable of refolding in a single explicit solvent MD trajectory in about 19 μs, indicating that the burst phase observed in experiments on the same mutant could produce native protein. The simulation reveals that after about 18.5 μs of conformational sampling, the productive structural rearrangement to the native state does not occur in a single swift step but is spread out over a brief series of helix and loop rearrangements that take about 0.9 μs. Our results support the molecular time scale inferred for λ-repressor from near-downhill folding experiments, where transition-state population can be seen experimentally, and also agrees with the transition-state transit time observed in slower folding proteins by single-molecule spectroscopy.

Original languageEnglish (US)
Pages (from-to)4265-4272
Number of pages8
JournalJournal of the American Chemical Society
Issue number11
StatePublished - Mar 19 2014

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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