The unbiased free energy profile associated with the rare event is obtained in accordance with Equation 5 by performing thermodynamic integration (TI) over the solvent averaged force ⟨fs(ξ′)⟩ξ′, i.e. the bare force of constraint (Lagrange multiplier) corrected by a mass metric tensor as derived by Sprik and Ciccotti. 𝛥Å ′ (5)