Abstract: In order to overcome the difficulty of applying dual Monte Carlo method to the bigger molecule system and off-lattice model, a simple new method of protein design based on relative entropy is proposed. This method completely based on the principles of Physics adopts the off-lattice model and takes 16 real protein in the natural and stable state as the target structure to test and design, of which the success rate can reach 75.9%. As compared with other studies employing the sequence space Monte Carlo technique, this method is more speedy and effective, and saves the time, to great extent, of searching sequence space, which can be seen as the simplification and improvement of the previous works of the same kind.