The major computational limitation of conventional ab initio methods is the scaling problem,because the cost of ab initio calculation scales as nth power or worse with the system size.The desire to study such large molecular systems has naturally led to the development of novel approximate methods,including semiempirical approaches,the hybrid quantum mechanical/molecular mechanical(QM/MM)methods,linear-scaling methods,and fragmentation methods.In the past two decades,the fragmentation method has opened a new door for the development of QM methods and their applications to large molecules.In this talk,I will describe molecular fractionation with conjugate caps(MFCC)based methods with applications to biomolecular systems.The MFCC approach was initially developed for calculating QM protein-ligand interaction energies and can also be used to calculate the full electron density and total energy of protein based on density functional theory(DFT).Recently,we developed the electrostatically embedded generalized molecular fractionation with conjugate caps(EE-GMFCC)method on top of the MFCC approach.By introducing the electrostatic embedding field for each fragment calculation and reducing the computational cost for long-range two-body QM interactions,the EE-GMFCC method is capable of accurately reproducing the molecular properties(such as dipole moment,electron density,and electrostatic potential),the total energy,and electrostatic solvation energy from full system QM calculations for proteins.The EE-GMFCC method has been applied for protein structure optimization,vibrational spectrum calculation,protein-ligand binding affinity prediction and ab initio molecular dynamics simulation of proteins.