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We develop a hybrid approach that combines the Monte Carlo (MC)method, a variational implicit-solvent model (VISM), and a binary level-set method forthe simulation of biomolecular binding in an aqueous solvent. The solvation free energy for the biomolecular complex is estimated by minimizing the VISM free-energy functional of all possible solute−solvent interfaces that are used as dielectric boundaries. This functional consists of the solute volumetric, solute−solvent interfacial, solute−solvent van der Waals interaction, and electrostatic free energy. A technique of shifting the dielectric boundary is used to accurately predict the electrostatic part of the solvation free energy.Minimizing such a functional in each MC move is made possible by our new and fast binary level-set method. This method is based on the approximation of surface area by the convolution of an indicator function with a compactly supported kernel and is implemented by simple flips of numerical grid cells locally around the solute−solvent interface. We apply our approach to the p53-MDM2 system for which the two molecules are approximated by rigid bodies. Our efficient approach captures some of the poses before the final bound state. All atom molecular dynamics simulations with most of such poses quickly reach the final bound state.Our work is a new step toward realistic simulations of biomolecular interactions. With further improvement of coarse graining and MC sampling, and combined with other models, our hybrid approach can be used to study the free-energy landscape and kinetic pathways of ligand binding to proteins.