By and large, biological processes involving ligand binding specificity, protein-protein association, protein-membrane association, protonation and unprotonation of ionizable groups, and macromolecular conformational changes, are given thermodynamically by a reversible work function, the free energy, or more generally by its configuration-dependent equivalent. A quantitative determination of free energies is, therefore, a problem of central importance in theoretical biophysics. Computational approaches at different levels of complexity and sophistication can be used to try and address this problem. Those range from (relatively expensive) molecular dynamics free energy simulations (MD/FES) based on all-atom models in which the solvent is treated explicitly to (relative inexpensive) Poisson-Boltzmann (PB) continuum electrostatic models in which the influence of the solvent is incorporated implicitly. The goal of this research is to refine and extend current computational approaches used in the modeling of biomolecular systems. More particularly, protocols that will provide increased accuracy and reliability in estimating free energies while remaining computationally tractable will be developed and tested. Progress in these computational methodologies is expected to have a great impact on the rational design of drugs and biomolecules.
