where 〈 𝑑𝑉 𝑑𝜆 〉 𝜆 is the average of the derivative of the coupling potential energy function (further referred to as the gradient time series for simplicity) assuming continuous λ. In practice, the integral is performed numerically using a discrete set {𝜆 𝑖 } 1 𝑁 where 〈 𝑑𝑉 𝑑𝜆 〉 𝑖 is the average of the gradient time series of the λi-window MD simulation, and wi is the statistical weight of the strata determined by the selected integration scheme.