Fold catastrophes and the dependence of free-energy barriers to conformational transitions on applied force

Abstract

Applied mechanical force (f) can activate conformational change in molecules by reducing the height of a free-energy barrier (ΔG b). In this paper, molecular dynamics simulations are carried out with umbrella sampling and self-consistent histogram methods to determine free-energy profiles for a coarse-grained model of a protein under an applied force. Applied force is shown to cause fold catastrophes, where free-energy minima are destabilized until they disappear. It is well-known that a fold catastrophe at force f = B implies the scaling ΔGb ≈ |B - f|3/2 in the limit of ΔGb → 0, but it is not clear whether this scaling is accurate for physically relevant barrier heights. The simulation results show that the fold catastrophe scaling is in fact accurate in the physically relevant regime and that the two-parameter function ΔGb = A(B - f)3/2 is superior to the two-parameter linear function for parametrizing changes in free-energy barriers with applied force. © 2010 American Chemical Society.