Spectral features of the ferrous-CO complex in cytochrome P450: a revisit using TDDFT calculations.

There are different views in the literature regarding how to interpret the observed spectral features of the ferrous-CO complexes in cytochrome P450 enzymes (P450s). In this work, we applied density functional theory (DFT) and time-dependent DFT (TDDFT) calculations at the B3LYP-D3BJ/def2-TZVP level with a CPCM correction to the ferrous-CO models of P450s as well as of proteins that contain a histidine-ligated heme. Our results support the notion derived from a previously reported iterative extended Hückel calculation that the involvement of the sulfur lone-pair orbital (S(nz)) of the axial cysteine ligand in the electronic excitations gives rise to a spectral anomaly. The Q and the shorter-wavelength Soret (B') peaks are primarily due to the electronic transitions from the a2u- and S(nz)-type molecular orbitals (MOs), generated via an orbital interaction of fragment orbitals, to the near-degenerate eg-type π* MOs, respectively. The transitions from the a1u-type MO to the eg-type MOs contribute most to the longer wavelength Soret (B) peaks. Both a2u- and S(nz)-type MOs contribute to the B peaks, but the contribution of the latter is greater. When the axial ligand is histidine, the Q and Soret peaks originate essentially from the excitations from the a2u- and a1u-type MOs to the eg-type MOs. The transitions from the b2u-type MOs to the eg-type MOs play the most significant role in the N peaks of such ferrous-CO complexes. Here, the b2u-type MOs have a large contribution from the imidazole π orbital.

The Bonding Nature of Fe-CO Complexes in Heme Proteins.

Although carbon monoxide (CO) has been known to bind to the ferrous heme in cytochrome P450 enzymes (P450s) since the earliest days of P450 research, details on the nature of the ferrous-CO bonding remain elusive. This study employed dispersion-corrected density functional theory (DFT) calculations and DFT-based theoretical analyses to investigate the complexes between CO and a thiolate- or imidazole-ligated heme that contains ferric or ferrous iron. Traditionally, the ferrous-CO bonding in heme systems has been interpreted qualitatively in terms of σ donation and π backdonation. Complementary occupied-virtual orbital pair (COVP) analysis yielded one orbital pair for σ donation and two for π backdonation together with the specific magnitude of their energetic contributions. The charge-transfer effect for these three orbital pairs has nearly the same energetic significance in the ferrous-CO complexes. Therefore, in total, the π-backdonation effect is much greater than the σ-donation effect. In contrast, the σ-donation effect is more significant in the ferric-CO complex because of the less efficient π backdonation. The nature of ferric-CO and ferrous-CO bonding was further scrutinized using the generalized Kohn-Sham energy decomposition analysis (GKS-EDA) scheme, whose results highlighted the significance of various effects in enhancing the Fe-CO bonding for the thiolate- and imidazole-ligated heme groups. In particular, the intrinsic repulsion effect plays a crucial role in promoting the preferential binding of CO toward the ferrous heme and in determining the geometry of the complexes.

On the force field optimisation of [Formula: see text]-lactam cores using the force field Toolkit.

When employing molecular dynamics (MD) simulations for computer-aided drug design, the quality of the used force fields is highly important. Here we present reparametrisations of the force fields for the core molecules from 9 different [Formula: see text]-lactam classes, for which we utilized the force field Toolkit and Gaussian calculations. We focus on the parametrisation of the dihedral angles, with the goal of reproducing the optimised quantum geometry in MD simulations. Parameters taken from CGenFF turn out to be a good initial guess for the multiplicity of each dihedral angle, but the key to a successful parametrisation is found to lie in the phase shifts. Based on the optimised quantum geometry, we come up with a strategy for predicting the phase shifts prior to the dihedral potential fitting. This allows us to successfully parameterise 8 out of the 11 molecules studied here, while the remaining 3 molecules can also be parameterised with small adjustments. Our work highlights the importance of predicting the dihedral phase shifts in the ligand parametrisation protocol, and provides a simple yet valuable strategy for improving the process of parameterising force fields of drug-like molecules.