A generalized linear response (GLR) method was developed and applied to hydration free energy calculations. According to this method, the atomic hydration can be described as a two-step process. In the first step a point particle is introduced into water, which, according to the scaled particle theory, creates a cavity with the size of a water molecule. The free energy change of this step for the simple point charge (SPC) water model can be calculated as 1.49kB T. In the second step the introduced point particle is transformed into a solute atom. The free energy change of this step can be calculated by the linear response approximation, which is applied to van der Waals and electrostatic interactions, as 〈V 〉0.5 . Here V is the solute-water interaction function, and 〈⋅⋅⋅〉0.5 denotes the ensemble average at the midpoint of the thermodynamic path between the point particle state and the hydration state. The GLR method was tested by the calculation of hydration free energies of several neutral organic compounds. The results of the calculation were in close agreement with the experiment and were also comparable with those obtained by the conventional free energy simulation method; the computational cost was decreased by about one order of magnitude. The GLR approach is more general than the existing linear response methods for free energy calculations because it applies the linear response approximation to electrostatic and van der Waals interactions and does not incorporate any empirically determined parameters. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 749-759, 1999.
Keywords: free energy calculations; hydration; linear response method; molecular dynamics simulations.