A　new　effective　and　fast　minimization　approach　completely　based　on　the　physical　theory　is　proposed　for　protein　design.　The　sequence　space　is　essentially　searched　according　to　the　Boltzmann　distribution.　In　this　approach,　the　relative　entropy　is　used　as　a　minimization　object　function.　The　method　has　been　tested　on　an　off-lattice　model　of　proteins　and　the　results　are　better　than　those　obtained　from　other　similar　work.　Therefore,　it　can　be　applied　as　a　uniform　frame　for　both　folding　and　inverse　folding　of　proteins.