Replica-exchange molecular dynamics (REMD) and their variants have been widely used in simulations of the biomolecular structure and dynamics. Replica exchange with solute tempering (REST) is one of the methods where temperature of a pre-defined solute molecule is exchanged between replicas, while solvent temperatures in all the replicas are kept constant. REST greatly reduces the number of replicas compared to the temperature REMD, while replicas at low temperatures are often trapped under their conditions, interfering with the conformational sampling. Here, we introduce a new scheme of REST, referred to as generalized REST (gREST), where the solute region is defined as a part of a molecule or a part of the potential energy terms, such as the dihedral-angle energy term or Lennard-Jones energy term. We applied this new method to folding simulations of a β-hairpin (16 residues) and a Trp-cage (20 residues) in explicit water. The protein dihedral-angle energy term is chosen as the solute region in the simulations. gREST reduces the number of replicas necessary for good random walks in the solute-temperature space and covers a wider conformational space compared to the conventional REST2. Considering the general applicability, gREST should become a promising tool for the simulations of protein folding, conformational dynamics, and an in silico drug design.