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  • Review Article
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Challenges in protein-folding simulations

Nature Physics volume 6, pages 751–758 (2010)Cite this article

Abstract

Experimental studies of protein folding are hampered by the fact that only low-resolution structural data can be obtained with sufficient temporal resolution. Molecular dynamics simulations offer a complementary approach, providing extremely high-resolution spatial and temporal data on folding processes. However, at present, such simulations are limited in several respects, including the inability of molecular dynamics force fields to completely reproduce the true potential energy surfaces of proteins, the need for simulations to extend to the millisecond timescale for the folding of many proteins and the difficulty inherent in obtaining sufficient sampling to properly characterize the extremely heterogeneous folding processes and then analysing those data efficiently. We review recent progress in the simulation of three common model systems for protein folding, and discuss how advances in technology and theory are allowing protein-folding simulations to address their present shortcomings.

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Figure 1: Cartoon representations of proteins discussed in this Review.
Figure 2: Representative snapshots of the trajectory followed by villin headpiece from the pre-folded intermediate to the native state.
Figure 3: Projections of a villin-folding trajectory (corresponding to WT-FOLD1 in Fig. 2) onto two-dimensional surfaces.
Figure 4: Directionality of hydrogen bonding in folding simulations.

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Acknowledgements

The field of molecular dynamics simulations of protein folding is so broad that it is impossible here to discuss the work of all major contributors, and thus we apologize to the (many) excellent investigators whose work could not be included because of space constraints. The authors are supported by grant P41-RR005969 from the National Institutes of Health and NSF PHY0822613 from the National Science Foundation. We thank A. Rajan for assistance in figure preparation, and C. Chipot for helping to refine our discussion of polarizable force fields.

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  1. Peter L. Freddolino

    Present address: Present address: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA,

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  1. Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA

    Peter L. Freddolino, Christopher B. Harrison, Yanxin Liu & Klaus Schulten

  2. Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA

    Yanxin Liu & Klaus Schulten

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Freddolino, P., Harrison, C., Liu, Y. et al. Challenges in protein-folding simulations. Nature Phys 6, 751–758 (2010). https://doi.org/10.1038/nphys1713

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