Calculation of solvation free-energy differences for large solute change from computer simulations with quadrature-based nearly linear thermodynamic integration Abstract: The free-energy simulation methodology is reviewed from the point of view of calculating large free-energy differences. The advantages of the nearly linear thermodynamic integration based on Gaussian quadrature are highlighted and its performance is characterized on systems ranging from the Lennard-Jones fluid to the A to B transition of DNA oligomers. A technique for optimizing the runlength at each quadrature point is given. Examples for the sensitivity of the calculated free energy to the atomic charges used are also presented.