Fig. 1.

Schematic representation of the free energy methods used here. a Thermodynamic integration simulations: on the left, different colours represent the individual MD simulations started sequentially at different λ points; on the right the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \partial {\rm H}/\partial \lambda $$\end{document} ensemble average and uncertainty is shown (free energy profile); these are used for the integration. b The Hamiltonian replica exchange simulations. The different replicas are started simultaneously and are allowed to exchange between λ points to obtain a better ensemble average. Replica 2 started from λ point 0.166 is marked with a thicker line to show how it visits all intermediate states. The boxed trajectory from different replicas was used to calculate the ensemble average for λ = 1.0