We propose a new approach to activated protein folding dynamics via a diffusive path integral framework. The important issues of kinetic paths in this situation can be directly addressed. This leads to the identification of the kinetic paths of the activated folding process, and provides a direct tool and language for the theoretical and experimental community to understand the problem better. ...

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Molecular dynamics simulations hold the promise of providing an atomic-level description of protein folding that cannot easily be obtained from experiments. Here, we examine the extent to which the molecular mechanics force field used in such simulations might influence the observed folding pathways. To that end, we performed equilibrium simulations of a fast-folding variant of the villin headp...

Most secreted bacterial proteases, including -lytic protease ( LP), are synthesized with covalently attached pro regions necessary for their folding. The LP folding landscape revealed that its pro region, a potent folding catalyst, is required to circumvent an extremely large folding free energy of activation that appears to be a consequence of its unique unfolding transition. Remarkably, the L...

The problem of how the linear amino acid sequence of a polypeptide folds to assume its unique tertiary structure is one of the most basic and challenging conundrums of contemporary science. Many of the principles and characteristics of protein folding have been learned by studying refolding of denatured polypeptides. However, the problem of protein folding cannot be completely understood withou...

Protein folding is a diffusional process, and the speed of folding is controlled by the frictional forces that act on the polypeptide chain. Several previous studies have suggested that the bulk viscosity of the solvent is the only important source of friction in folding reactions. By contrast, our studies of the folding dynamics of the Tryptophan Cage, a small, ultrafast-folding protein, show ...

Energetic frustration in protein folding is minimized by evolution to create a smooth and robust energy landscape. As a result the geometry of the native structure provides key constraints that shape protein folding mechanisms. Chain connectivity in particular has been identified as an essential component for realistic behavior of protein folding models. We study the quantitative balance of ene...

We used force-clamp atomic force microscopy to measure the end-to-end length of the small protein ubiquitin during its folding reaction at the single-molecule level. Ubiquitin was first unfolded and extended at a high force, then the stretching force was quenched and protein folding was observed. The folding trajectories were continuous and marked by several distinct stages. The time taken to f...

Understanding how kinetics in the unfolded state affects protein folding is a fundamentally important yet less well-understood issue. Here we employ three different models to analyze the unfolded landscape and folding kinetics of the miniprotein Trp-cage. The first is a 208 μs explicit solvent molecular dynamics (MD) simulation from D. E. Shaw Research containing tens of folding events. The sec...

The GroEL/ES chaperonin system functions as a protein folding cage. Many obligate substrates of GroEL share the (βα)8 TIM-barrel fold, but how the chaperonin promotes folding of these proteins is not known. Here, we analyzed the folding of DapA at peptide resolution using hydrogen/deuterium exchange and mass spectrometry. During spontaneous folding, all elements of the DapA TIM barrel acquire s...