We describe an implementation of the cluster-in-molecule(CIM) resolution of the identity(RI) approximation second-order M?ller–Plesset perturbation theory(CIM-RI-MP2), with the purpose of extending RI-MP2 calculations to very large systems. For typical conformers of several large polypeptides, we calculated their conformational energy differences with the CIM-RI-MP2 and the generalized energy-based fragmentation MP2(GEBF-MP2) methods, and compared these results with the density functional theory(DFT) results obtained with several popular functionals. Our calculations show that the conformational energy differences obtained with CIM-RI-MP2 and GEBF-MP2 are very close to each other. In comparison with the GEBF-MP2 and CIM-RI-MP2 relative energies, we found that the DFT functionals(CAM-B3LYP-D3, LC-?PBE-D3, M05-2X, M06-2X and ?B97XD) can give quite accurate conformational energy differences for structurally similar conformers, but provide less-accurate results for structurally very different conformers. We describe an implementation of the cluster-in-molecule (CIM) resolution of the identity (RI) approximation second-order Möller-Plesset perturbation theory (CIM-RI-MP2) very large systems. For typical conformers of several large polypeptides, we calculated their conformational energy differences with the CIM-RI-MP2 and the generalized energy-based fragmentation MP2 (GEBF-MP2) methods, and compared these results with the density functional theory ( DFT) results obtained with several popular functionals. Our calculations show that the conformational energy differences obtained with CIM-RI-MP2 and GEBF-MP2 are very close to each other. , we found that the DFT functionals (CAM-B3LYP-D3, LC-? PBE-D3, M05-2X, M06-2X and? B97XD) can give quite accurate conformational energy differences for structurally similar conformers, but with less-accurate results for structurally very diff erent conformers.