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Science 334 (6055): 517-520

Copyright © 2011 by the American Association for the Advancement of Science

How Fast-Folding Proteins Fold

Kresten Lindorff-Larsen,1,*,{dagger} Stefano Piana,1,*,{dagger} Ron O. Dror,1 David E. Shaw1,2,{dagger}

Abstract: An outstanding challenge in the field of molecular biology has been to understand the process by which proteins fold into their characteristic three-dimensional structures. Here, we report the results of atomic-level molecular dynamics simulations, over periods ranging between 100 μs and 1 ms, that reveal a set of common principles underlying the folding of 12 structurally diverse proteins. In simulations conducted with a single physics-based energy function, the proteins, representing all three major structural classes, spontaneously and repeatedly fold to their experimentally determined native structures. Early in the folding process, the protein backbone adopts a nativelike topology while certain secondary structure elements and a small number of nonlocal contacts form. In most cases, folding follows a single dominant route in which elements of the native structure appear in an order highly correlated with their propensity to form in the unfolded state.

1 D. E. Shaw Research, New York, NY 10036, USA.
2 Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA.

* These authors contributed equally to the manuscript.

{dagger} To whom correspondence should be addressed. E-mail: david.shaw{at}DEShawResearch.com (D.E.S.); kresten.lindorff-larsen{at}DEShawResearch.com (K.L.-L.); stefano.piana-agostinetti{at}DEShawResearch.com (S.P.)

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