Abstract Motivation Despite many successes, de novo protein design is not yet a solved problem as its success rate remains low. The low success rate is largely because we do not yet have an accurate energy function for describing the solvent-mediated interaction between amino acid residues in a protein chain. Previous studies showed that an energy function based on series expansions with its parameters optimized for side-chain and loop conformations can lead to one of the most accurate methods for side chain (OSCAR) and loop prediction (LEAP). Following the same strategy, we developed an energy function based on series expansions with the parameters optimized in four separate stages (recovering single-residue types without and with orientation dependence, selecting loop decoys and maintaining the composition of amino acids). We tested the energy function for de novo design by using Monte Carlo simulated annealing. Results The method for protein design (OSCAR-Design) is found to be as accurate as OSCAR and LEAP for side-chain and loop prediction, respectively. In de novo design, it can recover native residue types ranging from 38% to 43% depending on test sets, conserve hydrophobic/hydrophilic residues at ∼75%, and yield the overall similarity in amino acid compositions at more than 90%. These performance measures are all statistically significantly better than several protein design programs compared. Moreover, the largest hydrophobic patch areas in designed proteins are near or smaller than those in native proteins. Thus, an energy function based on series expansion can be made useful for protein design. Availability and implementation The Linux executable version is freely available for academic users at http://zhouyq-lab.szbl.ac.cn/resources/.