Consensus for the Fip35 folding mechanism?

Abstract

Recent advances in computational power and simulation programs finally delivered the first examples of reversible folding for small proteins with an all-atom description. But having at hand the atomistic details of the process did not lead to a straightforward interpretation of the mechanism. For the case of the Fip35 WW-domain where multiple long trajectories of 100 μs are available from D. E. Shaw Research, different interpretations emerged. Some of those are in clear contradiction with each other while others are in qualitative agreement. Here, we present a network-based analysis of the same data by looking at the local fluctuations of conventional order parameters for folding. We found that folding occurs through two major pathways, one almost four times more populated than the other. Each pathway involves the formation of an intermediate with one of the two hairpins in a native configuration. The quantitative agreement of our results with a state-of-the-art reaction coordinate optimization procedure as well as qualitative agreement with other Markov-state-models and different simulation schemes provides strong evidence for a multiple folding pathways scenario with the presence of intermediates.

The Role of Electrostatic Interactions in Folding of β-Proteins

“…A network based analysis supports these models, predicting that the pathway where the first loop is formed first is four times more probable. 65 Monte Carlo simulations in two course-grained models support this model and further find that the probability of each pathway is dependent on starting temperature and initial condition. 66 Three long time scale molecular dynamics simulations mimicking temperature jump conditions predict folding through the second hairpin; however, in one case the protein did not fully fold.…”

Dynamic heterogeneity in the folding/unfolding transitions of FiP35

“…FiP35 is a 35 residue protein consisting of two β-sheets connected by two loops (Fig. 1) and is the fastest-folding WW domain up to date which folds in ∼13 µs at 337 K. 31 The system has been studied both experimentally 32-34 and theoretically; 8,[12][13][14]35,36 in particular, Shaw et al have recently performed two 100 µs all-atom simulations of FiP35 in water that exhibited multiple folding/unfolding events. 12 Their result led to the conclusion of a single dominant folding pathway, and the folding rate and the native structure obtained from the trajectories were in agreement with the experimental results.…”

Nonparametric variational optimization of reaction coordinates

“…The dynamics is then described as diffusion on a low-dimensional free energy landscape, with both diffusion coefficient and free energy being functions of the coordinates. Examples of such dimensionality reductions can be found in a wide range of problems from many different scientific fields: in molecular dynamics simulations, 12,15,[17][18][19][20][21] order parameters in physics, 11,22 physically based RCs in single molecular experiments, 23,24 biomarkers in medicine, 25 analysing the game of chess, 26 to name a few.…”