Abstract
We present a quantum mechanical approach to study protein–ligand binding structure with application to a Adipocyte lipid‐binding protein complexed with Propanoic Acid. The present approach employs a recently develop molecular fractionation with a conjugate caps (MFCC) method to compute protein–ligand interaction energy and performs energy optimization using the quasi‐Newton method. The MFCC method enables us to compute fully quantum mechanical ab initio protein–ligand interaction energy and its gradients that are used in energy minimization. This quantum optimization approach is applied to study the Adipocyte lipid‐binding protein complexed with Propanoic Acid system, a complex system consisting of a 2057‐atom protein and a 10‐atom ligand. The MFCC calculation is carried out at the Hartree–Fock level with a 3‐21G basis set. The quantum optimized structure of this complex is in good agreement with the experimental crystal structure. The quantum energy calculation is implemented in a parallel program that dramatically speeds up the MFCC calculation for the protein–ligand system. Similarly good agreement between MFCC optimized structure and the experimental structure is also obtained for the streptavidin–biotin complex. Due to heavy computational cost, the quantum energy minimization is carried out in a six‐dimensional space that corresponds to the rigid‐body protein–ligand interaction. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1431–1437, 2004