Linking well-tempered metadynamics simulations with experiments

Abstract

Linking experiments with the atomistic resolution provided by molecular dynamics simulations can shed light on the structure and dynamics of protein-disordered states. The sampling limitations of classical molecular dynamics can be overcome using metadynamics, which is based on the introduction of a history-dependent bias on a small number of suitably chosen collective variables. Even if such bias distorts the probability distribution of the other degrees of freedom, the equilibrium Boltzmann distribution can be reconstructed using a recently developed reweighting algorithm. Quantitative comparison with experimental data is thus possible. Here we show the potential of this combined approach by characterizing the conformational ensemble explored by a 13-residue helix-forming peptide by means of a well-tempered metadynamics/parallel tempering approach and comparing the reconstructed nuclear magnetic resonance scalar couplings with experimental data.

Figure 1

Estimates of free-energy difference among the three S_α regions (see text) as a function of the simulation time for two independent PTMetaD simulations (open and closed).

Figure 2

FES as a function of S_α and S_SB from the open simulation. S_SB = [1 – (d/5.0)⁶]/[1 – (d/5.0)¹²], where d is the distance in Ångstroms between the Cδ of Glu² and the central carbon atom in the guanidine group of Arg¹⁰. Contour lines are plotted every k_BT.