Conformational changes of proteins upon ligand binding are usually explained in terms of several mechanisms including the induced fit, conformational selection, or their mixtures. Due to the slow time scales, conventional molecular dynamics (cMD) simulations based on the atomistic models cannot easily simulate the open-to-closed conformational transition in proteins. In our previous study, we have developed an enhanced sampling scheme (generalized replica exchange with solute tempering selected surface charged residues: gREST_SSCR) for multidomain proteins and applied it to ligand-mediated conformational changes in the G134R mutant of ribose-binding protein (RBPG134R) in solution. The free-energy landscape (FEL) of RBPG134R in the presence of a ribose at the binding site included the open and closed states and two intermediates, open-like and closed-like forms. Only the open and open-like forms existed in the FEL without a ribose. In the current study, the coupling between the conformational changes and ligand binding is further investigated using coarse-grained MD, multiple atomistic cMD, and free-energy calculations. The ribose is easily dissociated from the binding site of wild-type RBP and RBPG134R in the cMD simulations starting from the open and open-like forms. In contrast, it is stable at the binding site in the simulations from the closed and closed-like forms. The free-energy calculations provide the binding affinities of different structures, supporting the results of cMD simulations. Importantly, cMD simulations from the closed-like structures reveal transitions toward the closed one in the presence of a bound ribose. On the basis of the computational results, we propose a molecular mechanism in which conformational selection and induced fit happen in the first and second halves of the open-to-closed transition in RBP, respectively.