The representation of chlorine, bromine, and iodine in aryl halides has been modified in the OPLS-AA and OPLS/CM1A force fields in order to incorporate halogen bonding. The enhanced force fields, OPLS-AAx and OPLS/CM1Ax, have been tested in calculations on gas-phase complexes of halobenzenes with Lewis bases, and for free energies of hydration, densities, and heats of vaporization of halobenzenes. Comparisons with results of MP2/aug-cc-pVDZ(-PP) calculations for the complexes are included. Implementation in the MCPRO software also allowed computation of relative free energies of binding for a series of HIV reverse transcriptase inhibitors via Monte Carlo/free-energy perturbation calculations. The results support the notion that the activity of an unusually potent chloro analog likely benefits from halogen bonding with the carbonyl group of a proline residue.

Halogen bonds, the formally noncovalent interactions where the halogen acts as a Lewis acid, have brought several controversies to the theoretical world regarding its nature and components, e.g., charge transfer (CT), electrostatics, dispersion, and polarization. The debate on whether all characteristics are accounted for by electrostatics is examined, highlighting the importance of the CT and repulsive interactions. A number of strongly halogen‐bonded complexes are as covalent as metal–ligand coordination bonds. Different levels of computational methods are reviewed with the objective of finding the best accuracy/cost ratios. The unusual electronic anisotropy of the halogen donor and its interaction with a Lewis base demand specific calculation schemes. From the wave‐function theory methods, only the ones with empirical corrections (spin‐component‐scaled MP2 or CCSD, and MP2.5) are suitable when CCSD(T) is unattainable. Density functional theory functionals with a high amount of exact exchange are fast and reliable methods for halogen bonds, but double hybrids are more robust if other types of interactions are involved. Molecular mechanics methods can be useful, but only when specific corrections are added to compensate for the inability of such methods to describe CT. The most common method introduces a virtual site with a partial positive charge to account for the quantum chemical effect of the halogen bond. This methodology has been successfully applied to study protein–ligand interactions for drug design. WIREs Comput Mol Sci 2014, 4:523–540. doi: 10.1002/wcms.1189 This article is categorized under: Structure and Mechanism > Molecular Structures Structure and Mechanism > Computational Biochemistry and Biophysics Theoretical and Physical Chemistry > Thermochemistry

Dopamine can be generated from tyramine via arene hydroxylation catalyzed by a cytochrome P450 enzyme (CYP2D6). Our quantum mechanical/molecular mechanical (QM/MM) results reveal the decisive impact of the protein in selecting the 'best' reaction mechanism. Instead of the traditional Meisenheimer-complex mechanism, the study reveals a mechanism involving an initial hydrogen atom transfer from the phenolic hydroxyl group of the tyramine to the iron-oxo of the compound I (Cpd I), followed by a ring-π radical rebound that eventually leads to dopamine by keto-enol rearrangement. This mechanism is not viable in the gas phase since the O-H bond activation by Cpd I is endothermic and the process does not form a stable intermediate. By contrast, the in-protein reaction has a low barrier and is exothermic. It is shown that the local electric field of the protein environment serves as a template that stabilizes the intermediate of the H-abstraction step and thereby mediates the catalysis of dopamine formation at a lower energy cost. Furthermore, it is shown that external electric fields can either catalyze or inhibit the process depending on their directionality.

It is shown that H-abstraction reactivity by oxoiron(IV) complexes with a quintet ground state is highly enhanced due to exchange-stabilization endowed by the increased number of the exchange Correspondence to: Lawrence Que, Jr, larryque@umn.edu; Sason Shaik, sason@yfaat.ch.huji.ac.il. One of us, [6] has recently prepared two such S=2 reagents and compared their H-abstraction activities to those of the synthetic complexes that possess the more common S=1 ground state. These results generated however, a bag full of surprises, which are addressed herein by means of DFT calculations. Shown in Figure 1 are DFT calculated iron(IV)-oxo complexes along with their key geometric features, and spin state information. The isolated complex with an S=2 ground state is TMG 3 trenFe(IV)O 2+ (1),[6a] which possesses a trigonal bipyramidal iron coordination, typified by two-below-two-below-one d-orbital block, [3b] and hence a quintet ground state, well below the S=1 state. Surprisingly, however, 1 exhibited a rather sluggish H-abstraction reactivity even towards the weak C-H bonds of 1,4-cyclohexadiene (CHD). Thus, 1 was slightly less reactive than N4PyFe(IV)O 2+ 2 and five times more reactive than TMC(AN)Fe(IV)O 2+ , 3;[6b] both of which are thought to react via TSR. NIH Public Access[4] To add to the puzzle, the putative Tp(OBz)Fe(IV)O, 4, which was proposed to form upon oxygenation of Tp(benzoylformate)Fe(II) as a model for TauD, was found to be highly reactive and capable of activating even the strong C-H bond of cyclopentane (BDE = 96.3 kcal mol −1 ).[6b] Note that in the S=2 state, 5 4, Fe loses one of the benzoate arms and becomes a pentacoordinated square pyramid with a basal Fe(IV)-oxo moiety (Fig. 1). Thus, it is this weaker ligand field that stabilizes S=2 relative to the hexacoordinated S=1. Indeed, as can be seen from Figure 1, 4 is computed to involve degenerate S=1 and S=2 states.[7] So, in 4 a competition is expected between the two spin states to effect C-H activation; which state dominates? In summation, the experimental relative reactivities of the four Fe=O reagents order in a puzzling sequence:What is the origin of this reactivity pattern, and what are the electronic and steric factors that shape this trend? Answering this question is important for establishing rules of design of effective catalysts for C-H activation.To answer these questions we studied the reactivities of 1-4 towards H-abstraction from CHD. The geometries of all the critical species along the H-abstraction paths of 1-3, which are di-positively charged, were optimized at the B3LYP/B1(CH 3 CN) (B1 is LACVP) level at the reaction solvent, to minimize self-interaction errors which cause artificial electron transfer in some of these systems.[8] For 4, which is neutral and hence less subject to these particular errors, [8] we used B3LYP/B1. All energies were subsequently estimated using a NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript larger basis set, B2 (B2 is LACV3P+*), and solvent corrections, using th...

The frequency of biaryl substructures in a database of approved oral drugs has been analyzed. This led to designation of 20 prototypical biaryls plus 10 arylpyridinones for parameterization in the OPLS all-atom force fields. Bond stretching, angle-bending, and torsional parameters were developed to reproduce the MP2 geometries and torsional energy profiles. The transferability of the new parameters was tested through their application to three additional biaryls. The torsional energetics for the 33 biaryl molecules are analyzed and factors leading to preferences for planar and non-planar geometries are identified. For liquid biphenyl, the computed density and heat of vaporization at the boiling point (255 C) are also reported.