A “slow” protein folds quickly in the end

Abstract

Until just a few years ago, it was not clear whether it would be possible to fold proteins using all-atom molecular dynamics simulations with explicit solvent molecules, despite the insights that these simulations had yielded into other biological problems. This was not just because of the computational challenge of reaching folding time scales, typically microseconds to seconds or longer, but also because it was not generally accepted that the empirical energy functions (“force fields”) used were sufficiently accurate to locate the folded state as a global free-energy minimum. This has changed dramatically in the last 2 y, with the development by Shaw and coworkers of a special-purpose supercomputer, Anton, capable of running biomolecular MD simulations on a microsecond or even millisecond timescale (1). This group showed that, with only minor adjustments to existing force fields (2⇓–4), it was possible to fold 12 small, “fast-folding” proteins (1), which adopt their native structure in microseconds. At the time, it was still not clear, however, whether it would be possible to do the same for larger, slower-folding proteins (5, 6). In PNAS, Piana et al. report simulations of ubiquitin folding, which occurs in milliseconds (7). Their results not only extend the computationally accessible time scale for calculating equilibrium folding trajectories by 2–3 orders of magnitude but have a number of implications that can only be deduced from a comparison of fast and slow folding proteins.