Calculation of electrostatic free energy for the nonlinear Poisson-Boltzmann model based on the dimensionless...

The Poisson-Boltzmann (PB) equation governing the electrostatic potential with a unit is often transformed to a normalized form for a dimensionless potential in numerical studies. To calculate the electrostatic free energy (EFE) of biological interests, a unit conversion has to be conducted, because the existing PB energy functionals are all described in terms of the original potential. To bypass this conversion, this paper proposes energy functionals in terms of the dimensionless potential for the first time in the literature, so that the normalized PB equation can be directly derived by using the Euler-Lagrange variational analysis. Moreover, alternative energy forms have been rigorously derived to avoid approximating the gradient of singular functions in the electrostatic stress term. A systematic study has been carried out to examine the surface integrals involved in alternative energy forms and their dependence on finite domain size and mesh step size, which leads to a recommendation on the EFE forms for efficient computation of protein systems. The calculation of the EFE in the regularization formulation, which is an analytical approach for treating singular charge sources of the PB equation, has also been studied. The proposed energy forms have been validated by considering smooth dielectric settings, such as diffuse interface and super-Gaussian, for which the EFE of the nonlinear PB model is found to be significantly different from that of the linearized PB model. All proposed energy functionals and EFE forms are designed such that the dimensionless potential can be simply plugged in to compute the EFE in the unit of kcal/mol, and they can also be applied in the classical sharp interface PB model.