Generalized Hybrid‐Orbital Method for Combining Density Functional Theory with Molecular Mechanicals

The generalized hybrid orbital (GHO) method has previously been formulated for combining molecular mechanics with various levels of quantum mechanics, in particular semiempirical neglect of diatomic differential overlap theory, ab initio Hartree–Fock theory, and self‐consistent charge density functional tight‐binding theory. To include electron‐correlation effects accurately and efficiently in GHO calculations, we extend the GHO method to density functional theory in the generalized‐gradient approximation and hybrid density functional theory (denoted by GHO‐DFT and GHO‐HDFT, respectively) using Gaussian‐type orbitals as basis functions. In the proposed GHO‐(H)DFT formalism, charge densities in auxiliary hybrid orbitals are included to calculate the total electron density. The orthonormality constraints involving the auxiliary Kohn–Sham orbitals are satisfied by carrying out the hybridization in terms of a set of Löwdin symmetrically orthogonalized atomic basis functions. Analytical gradients are formulated for GHO‐(H)DFT by incorporating additional forces associated with GHO basis transformations. Scaling parameters are introduced for some of the one‐electron integrals and are optimized to obtain the correct charges and geometry near the QM/MM boundary region. The GHO‐(H)DFT method based on the generalized gradient approach (GGA) (BLYP and mPWPW91) and HDFT methods (B3 LYP, mPW1PW91, and MPW1 K) is tested—for geometries and atomic charges—against a set of small molecules. The following quantities are tested: 1) the C C stretch potential in ethane, 2) the torsional barrier for internal rotation around the central C C bond in n ‐butane, 3) proton affinities for a set of alcohols, amines, thiols, and acids, 4) the conformational energies of alanine dipeptide, and 5) the barrier height of the hydrogen‐atom transfer between n ‐C 4 H 10 and n ‐C 4 H 9 , where the reaction center is described at the MPW1 K/6–31G(d) level of theory.