1. Biophysics Program and Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA
2. Departments of Chemistry and Physics, and Center for Biophysics and Computational Biology, University of Illinois, Urbana, Illinois 61801, USA
3. These authors contributed equally to this work

Correspondence to: Vijay S. Pande¹Martin Gruebele³ Correspondence and requests for materials should be addressed to V.S.P. (e-mail: Email: pande@stanford.edu) or M.G. (e-mail: Email: gruebele@scs.uiuc.edu).

Abstract

Protein folding is difficult to simulate with classical molecular dynamics. Secondary structure motifs such as -helices and -hairpins can form in 0.1–10 s (ref. 1), whereas small proteins have been shown to fold completely in tens of microseconds². The longest folding simulation to date is a single 1-s simulation of the villin headpiece³; however, such single runs may miss many features of the folding process as it is a heterogeneous reaction involving an ensemble of transition states^{4, 5}. Here, we have used a distributed computing implementation to produce tens of thousands of 5–20-ns trajectories (700 s) to simulate mutants of the designed mini-protein BBA5. The fast relaxation dynamics these predict were compared with the results of laser temperature-jump experiments. Our computational predictions are in excellent agreement with the experimentally determined mean folding times and equilibrium constants. The rapid folding of BBA5 is due to the swift formation of secondary structure. The convergence of experimentally and computationally accessible timescales will allow the comparison of absolute quantities characterizing in vitro and in silico (computed) protein folding⁶.

1. Biophysics Program and Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA
2. Departments of Chemistry and Physics, and Center for Biophysics and Computational Biology, University of Illinois, Urbana, Illinois 61801, USA
3. These authors contributed equally to this work

Correspondence to: Vijay S. Pande¹Martin Gruebele³ Correspondence and requests for materials should be addressed to V.S.P. (e-mail: Email: pande@stanford.edu) or M.G. (e-mail: Email: gruebele@scs.uiuc.edu).