Quantitative comparison of villin headpiece subdomain simulations and triplet–triplet energy transfer experiments.

K. Beauchamp, D. Ensign, R. Das, and V. S. Pande.

Proceedings of the National Academy of Sciences, USA, in press (2011)

We are constantly honing our methods to improve Folding@home’s ability to predict the behavior of proteins. This paper demonstrates the current state of the art in terms of both sampling and analysis. When compared to detailed TTET experiments, we show that our methods can piece out even fairly detailed aspects of folding. However, we also see the ways in which our models are not perfect, suggesting how we can improve our methods even further.

As the fastest folding protein, the villin headpiece (HP35) serves as an important bridge between simulation and experimental studies of protein folding. Despite the simplicity of this system, experiments continue to reveal a number of surprises, including structure in the unfolded state and complex equilibrium dynamics near the native state. Using 2.5 ms of molecular dynamics and Markov state models, we connect to current experimental results in three ways. First, we present and validate a novel method for the quantitative prediction of triplet–triplet energy transfer experiments. Second, we construct a many-state model for HP35 that is consistent with previous experiments. Finally, we predict contact-formation time traces for all 1,225 possible triplet–triplet energy transfer experiments on HP35.