Author(s): De Sancho D, Mittal J, Best RB
Abstract Share this page
Abstract The C-terminal β-hairpin of protein G is a 16-residue peptide that folds in a two-state fashion akin to many larger proteins. However, with an experimental folding time of ∼6 μs, it remains a challenging system for all-atom, explicitly solvated, molecular dynamics simulations. Here, we use a large simulation data set (0.7 ms total) of the hairpin at 300 and 350 K to interpret its folding via a master equation approach. We find a separation of over an order of magnitude between the longest and second longest relaxation times, with the slowest relaxation corresponding to folding. However, in spite of this apparent two-state dynamics, the folding rate determined based on a first-passage time analysis depends on the initial conditions chosen, with a nonexponential distribution of first passage times being obtained in some cases. Using the master equation model, we are now able to account quantitatively for the observed distribution of first passage times. The deviation from the expected exponential distribution for a two-state system arises from slow dynamics in the unfolded state, associated with formation and melting of helical structures. Our results help to reconcile recent findings of slow dynamics in unfolded proteins with observed two-state folding kinetics. At the same time, they indicate that care is required in estimating folding kinetics from many short folding simulations. Last, we are able to use the master equation model to obtain details of the folding mechanism and folding transition state, which appear consistent with the "zipper" mechanism inferred from the experiment.
This article was published in J Chem Theory Comput
and referenced in Journal of Glycomics & Lipidomics