We report here our recent progresses in the development and application of multi-resolution and multi-canonical ensemble methods for improving the phase space sampling of complex systems.Specifically,we developed an adaptive multi-resolution method in which fine-grained atomic and coarse-grained models are combined to describe the interaction of biomolecular systems.The method provides improved computational efficiency as compared to atomistic simulations,yet maintains accurate description of the structural and dynamics properties.To address the complicated thermodynamics of multisite proton binding in biomolecules,we also developed a multi-canonical ensemble method which allows the simultaneous simulation of 2N protonation states of the target molecule.This method becomes essentially for the first time an in silico concurrent multisite pH titration of protein molecules.Application results of both methods will be reported.