TCB Publications - Abstract

Yanxin Liu, Maxim B. Prigozhin, Klaus Schulten, and Martin Gruebele. Observation of complete pressure-jump protein refolding in molecular dynamics simulation and experiment. Journal of the American Chemical Society, 136:4265-4272, 2014.

LIU2014 Density is an easily adjusted variable in molecular dynamics simulations (MD). Thus pressure 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 pressure jump is not necessarily faster than that after a temperature jump. Recent P-jump refolding experiments of the helix bundle $\lambda$- repressor have shown evidence of a < 3 $\mu$s burst phase, but also of a 1.5 ms 'slow' phase of refolding, attributed to non-native helical structure frustrating $\mu$s refolding. Here we show that a $\lambda$-repressor mutant is nonetheless capable of refolding in a single explicit solvent MD trajectory in about 19 $\mu$s, indicating that the burst phase observed in experiments on the same mutant could produce native protein. The simulation reveals that after about 18.5 $\mu$s 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 $\mu$s. Our results support the molecular time scale inferred for $\lambda$-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.

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