A virtual system-coupled molecular dynamics simulation free from experimental knowledge on binding sites: Application...

Ligand-receptor docking simulation is difficult when the biomolecules have high intrinsic flexibility. If some knowledge on the ligand-receptor complex structure or inter-molecular contact sites are presented in advance, the difficulty of docking problem considerably decreases. This paper proposes a generalized-ensemble method "cartesian-space division mD-VcMD" (or CSD-mD-VcMD), which calculates stable complex structures without assist of experimental knowledge on the complex structure. This method is an extension of our previous method that requires the knowledge on the ligand-receptor complex structure in advance. Both the present and previous methods enhance the conformational sampling, and finally produce a binding free-energy landscape starting from a completely dissociated conformation, and provide a free-energy landscape. We applied the present method to same system studied by the previous method: A ligand (ribocil A or ribocil B) binding to an RNA (the aptamer domain of the FMN riboswitch). The two methods produced similar results, which explained experimental data. For instance, ribocil B bound to the aptamer's deep binding pocket more strongly than ribocil A did. However, this does not mean that two methods have a similar performance. Note that the present method did not use the experimental knowledge of binding sites although the previous method was supported by the knowledge. The RNA-ligand binding site could be a cryptic site because RNA and ligand are highly flexible in general. The current study showed that CSD-mD-VcMD is actually useful to obtain a binding free-energy landscape of a flexible system, i.e., the RNA-ligand interacting system.