TY - JOUR

T1 - How robust are protein folding simulations with respect to force field parameterization?

AU - Piana, Stefano

AU - Lindorff-Larsen, Kresten

AU - Shaw, David E

N1 - Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

PY - 2011

Y1 - 2011

N2 - Molecular dynamics simulations hold the promise of providing an atomic-level description of protein folding that cannot easily be obtained from experiments. Here, we examine the extent to which the molecular mechanics force field used in such simulations might influence the observed folding pathways. To that end, we performed equilibrium simulations of a fast-folding variant of the villin headpiece using four different force fields. In each simulation, we observed a large number of transitions between the unfolded and folded states, and in all four cases, both the rate of folding and the structure of the native state were in good agreement with experiments. We found, however, that the folding mechanism and the properties of the unfolded state depend substantially on the choice of force field. We thus conclude that although it is important to match a single, experimentally determined structure and folding rate, this does not ensure that a given simulation will provide a unique and correct description of the full free-energy surface and the mechanism of folding.

AB - Molecular dynamics simulations hold the promise of providing an atomic-level description of protein folding that cannot easily be obtained from experiments. Here, we examine the extent to which the molecular mechanics force field used in such simulations might influence the observed folding pathways. To that end, we performed equilibrium simulations of a fast-folding variant of the villin headpiece using four different force fields. In each simulation, we observed a large number of transitions between the unfolded and folded states, and in all four cases, both the rate of folding and the structure of the native state were in good agreement with experiments. We found, however, that the folding mechanism and the properties of the unfolded state depend substantially on the choice of force field. We thus conclude that although it is important to match a single, experimentally determined structure and folding rate, this does not ensure that a given simulation will provide a unique and correct description of the full free-energy surface and the mechanism of folding.

U2 - 10.1016/j.bpj.2011.03.051

DO - 10.1016/j.bpj.2011.03.051

M3 - Journal article

C2 - 21539772

VL - 100

SP - L47-L49

JO - Biophysical Journal

JF - Biophysical Journal

SN - 0006-3495

IS - 9

ER -