Due to recent advances of computer power, algorithms, and force fields, many molecular dynamics (MD) studies have demonstrated that it is now possible to solve various molecular biology problems. In all-atom MD simulations, not only proteins but also water molecules are explicitly represented with the physics-based force field at the atomic level. Although the MD simulations provide atomic-level insight into the biomolecular processes, they require huge computational resource. In Japan, K computer, which reaches 10 PFlops, is now available for scientific studies.
In this work, we investigate the molecular recognition mechanism of protein. For a ligand binding its target protein, Prof. Fujitani, one of our collaborators, developed an accurate binding free energy calculation protocol named MP-CAFEE.1,2 In the case of FKBP, the error of the free energy prediction was smaller than 1 kcal/mol. We apply the protocol to several systems to discover the molecular recognition mechanism. We find that only one mono-methylation can affect the binding free energy, which is a good indicator of the molecular recognition. Interestingly, our analysis suggests that the role of water is crucial.
We expect that these methodological and theoretical progresses can be applied to the drug design. In this study, we also try to apply MP-CAFEE to the selection of drug candidates targeting for a cancer-associated protein.3 To conduct the MP-CAFEE procedures for many compounds, huge computational power is required. By using K computer, we find out several potential drug candidates, which will be examined experimentally in future.