Limited searching in the conformational space is one of the major obstacles for investigating protein dynamics by numerical approaches. For this reason, classical all-atom mol. dynamics (MD) simulations of proteins tend to be confined to local energy min., particularly when the bulk solvent is treated explicitly. To overcome this problem, we have developed a novel replica exchange protocol that uses modified force-field parameters to treat interparticle nonbonded potentials within the protein and between protein and solvent atoms, leaving unperturbed those relative to solvent-solvent interactions. We have tested the new protocol on the 18-residue-long tip of the P domain of calreticulin in an explicit solvent. With only eight replicas, we have been able to considerably enhance the conformational space sampled during a 100 ns simulation, compared to as many parallel classical mol. dynamics simulations of the same length or to a single one lasting 450 ns. A direct comparison between the various simulations has been possible thanks to the implementation of the weighted histogram anal. method, by which conformations simulated with modified force-field parameters can be assigned different wts. Interatom, inter-residue distances in the structural ensembles obtained with our novel replica exchange approach and by classical MD simulations compare equally well with those derived from NMR data. Rare events, such as unfolding and refolding, occur with reasonable statistical frequency. Visiting of conformations characterized by very small Boltzmann wts. is also possible. Despite their low probability, such regions of the conformational space may play an important role in the search for local potential-energy min. and in dynamically controlled functions. [on SciFinder (R)]