Font Size: 

We recently provided a new computational scheme for evaluating the standard free energy of binding for biomolecular systems, based on the calculation of the potential of mean force (PMF) from umbrella sampling simulations along the reaction coordinates of the curvilinear dissociation pathways.  We provided a tailor-made theoretical framework based on statistical mechanics of binding equilibrium for such simulations.  A simple variational principle is applied to determine the lower-bound PMF, which is subsequently used to derive the standard free energy of binding.  We have benchmarked our method with the well-studied barnase-barstar system, which is a classic example for protein-protein interactions.  We found that the two major dissociation pathways determined with our approach agree very well with the recent millisecond timescale adaptive molecular dynamics simulations, which involves interactions with the RNA-binding loop and the Val 36 to Gly 40 loop, respectively.  Our approach has also been used to discriminate the decoys from protein-protein docking studies.  We have also applied this method to other protein-protein systems, and protein-small molecule and protein-peptide systems.  We anticipate that our method would pave the way for further drug design, protein design, and other biological applications.