A computational method to investigate the global conformational change of a protein is proposed by combining the linear response path following (LRPF) method and three”¾dimensional reference interaction site model (3D”¾RISM) theory, which is referred to as the LRPF/3D”¾RISM method. The proposed method makes it possible to efficiently simulate protein conformational changes caused by either solutions of varying concentrations or the presence of cosolvent species by taking advantage of the LRPF and 3D”¾RISM. The proposed method is applied to the urea”¾induced denaturation of ubiquitin. The LRPF/3D”¾RISM trajectories successfully simulate the early stage of the denaturation process within the simulation time of 300 ns, whereas no significant structural change is observed even in the 1 μs standard MD simulation. The obtained LRPF/3D”¾RISM trajectories reproduce the mechanism of the urea denaturation of ubiquitin reported in previous studies, and demonstrate the high efficiency of the method.