Small mechanical forces play important functional roles in many crucial
cellular processes, including in the dynamical behavior of the cytoskeleton and
in the regulation of osmotic pressure through membrane-bound proteins.
Molecular simulations offer the promise of being able to design the behavior of
proteins that sense and respond to these forces. However, it is difficult to
predict and identify the effect of the relevant piconewton (pN) scale forces
due to their small magnitude. Previously, we introduced the Infinite Switch
Simulated Tempering in Force (FISST) method which allows one to estimate the
effect of a range of applied forces from a single molecular dynamics
simulation, and also demonstrated that FISST additionally accelerates sampling
of a molecule's conformational landscape. For some problems, we find that this
acceleration is not sufficient to capture all relevant conformational
fluctuations, and hence here we demonstrate that FISST can be combined with
either temperature replica exchange or solute tempering approaches to produce a
hybrid method that enables more robust prediction of the effect of small forces
on molecular systems.Comment: 15 Pages with 6 figures, plus 7 supplemental figures and one
supplemental tabl