Thursday, August 23, 2012

Refinement of protein structure homology models via long, all-atom molecular dynamics simulations

Alpan Raval, Stefano Piana, Michael P. Eastwood, Ron O. Dror, and David E. Shaw, Proteins 2012, 80, 2071-2079 (Paywall)
Contributed by Victor Guallar

Many theoretical chemists work routinely on biological systems and, in particular, on proteins. While it might not be their main interest, predicting the conformational sampling associated to these systems is certainly a concern.  Those who have been around for a while have seen how the necessary conformational sampling has moved from few picoseconds to hundreds of nanoseconds and even microseconds (while I do not agree, molecular dynamics has almost the exclusivity as a sampling technique). Clearly the latest development of special-purpose computers, such as the remarkable effort from the D. E. Shaw Research group, together with the development of molecular dynamics for graphical processing units, have contributed to this time expansion. Along these advances we surely had the following questions: are the force fields up to it?, how meaningful are these long molecular dynamics simulations?

The Shaw group has probably already answered these questions for us. In a comprehensive study1 they produce at least a hundred microseconds simulation for 24 proteins used in recent CASP competitions. They frame their study under the capabilities of molecular dynamics (and force fields) in refining homology models. Thus, for each system they produce a trajectory from both an initial homology model and from the native X-ray structure (or NMR). This study followed a previous one where the simulations were capable of accurately reproducing the native state on several fast-folders. The results this time, however, are quite surprising and even worrisome. For most of the systems the structures drift away from the native state. Furthermore, this drift occurs even when starting from the native state. Overall the results indicate that for most systems the force field minimum is not consistent with the X-ray or NMR experimental structures. While the authors only used two force fields (considered to be the best ones), they conclude that most likely this is a limitation for all available force fields.

The authors obtain better results when imposing constraints to the simulation (limiting the drift away from the native structure). Thus, one can conclude from this work that brute force molecular dynamics simulations are still far away from being accurate. Obviously similar conclusion could be applied to other sampling techniques using the same force fields (for example Monte Carlo techniques). While we wait for better force fields (maybe polarizable ones such AMOEBA?), we probably should use molecular dynamics as a local exploration rather than to predict novel conformations, or to score significantly different ones. Of course these limitations might not apply to those systems with a strong preference for a state, such as fast-folder proteins.

Alpan Raval, Stefano Piana, Michael P. Eastwood,Ron O. Dror, and David E. ShawProteins 2012, 80, 2071-2079 


  1. Do you think the structures *should* stay near the NMR or X-ray structures? Could it not be that the simulations are merely beginning to sample the range of different structures accessible to a protein in solution, and have not converged yet (hence appearing to continually drift away)?

    1. Jane, as Lipi says below (and the authors in the paper) it seems like simulations are converged. Many homology and native runs visit similar space (which is different from the experimental). Also, the fact that the native starts from the crystal and moves significantly away is disturbing. The authors only find a weak correlation with crystal contacts, meaning that the difference between the crystal packing and solution can only explain a small part of the differences.
      Also looking at the language that the authors use in the paper, it denotes quite a disappointment from them (a contagious one I must say). I guess they are the ones with the best information and surely they will keep producing excellent paper addressing this issue.

  2. Rigorous work is urgently required on presently used force-fields to improve the accuracy. The above mentioned simulations are sufficiently sampled and therefore the drift is not a consequence of convergence. Consequently, such large scale simulations will always be fruitful in improvement of present techniques!

  3. Gert Vriend in Proteins 47:393 came up with the same conclusion about the conventional force fields, and suggested "self-parametrizing" force field.