Marek Freindorf

Optimization of the Lennard-Jones parameters for a combined ab initio quantum mechanical and molecular mechanical potential using the 3-21G basis set

A combined ab initio quantum mechanical and molecular mechanical (AI‐QM/MM) potential for use in molecular modeling and simulation has been described. In this article, we summarize a procedure for deriving the empirical parameters embedded in a combined QM/MM model and suggest a set of Lennard‐Jones parameters for the combined ab initio 3‐21G and MM OPLS‐TIP3P (AI‐3/MM) potential. Interaction energies and geometrical parameters predicted with the AI‐3/MM model for over 80 hydrogen‐bonded complexes of organic compounds with water were found to be in good accord with ab initio 6‐31G(d) results. We anticipate that the AI‐3/MM potential should be reasonable for use in condensed phase simulations.

Lennard–Jones parameters for the combined QM/MM method using the B3LYP/6‐31G*/AMBER potential

A combined DFT quantum mechanical and AMBER molecular mechanical potential (QM/MM) is presented for use in molecular modeling and molecular simulations of large biological systems. In our approach we evaluate Lennard–Jones parameters describing the interaction between the quantum mechanical (QM) part of a system, which is described at the B3LYP/6‐31+G* level of theory, and the molecular mechanical (MM) part of the system, described by the AMBER force field. The Lennard–Jones parameters for this potential are obtained by calculating hydrogen bond energies and hydrogen bond geometries for a large set of bimolecular systems, in which one hydrogen bond monomer is described quantum mechanically and the other is treated molecular mechanically. We have investigated more than 100 different bimolecular systems, finding very good agreement between hydrogen bond energies and geometries obtained from the combined QM/MM calculations and results obtained at the QM level of theory, especially with respect to geometry. Therefore, based on the Lennard–Jones parameters obtained in our study, we anticipate that the B3LYP/6‐31+G*/AMBER potential will be a precise tool to explore intermolecular interactions inside a protein environment.

Enhancement of hydrophobic interactions and hydrogen bond strength by cooperativity: synthesis, modeling, and molecular dynamics simulations of a congeneric series of thrombin inhibitors.

Accurately predicting the binding affinity of ligands to their receptors by computational methods is one of the major challenges in structure-based drug design. One of the potentially significant errors in these predictions is the common assumption that the ligand binding affinity contributions of noncovalent interactions are additive. Herein we present data obtained from two separate series of thrombin inhibitors containing hydrophobic side chains of increasing size that bind in the S3 pocket and with, or without, an adjacent amine that engages in a hydrogen bond with Gly 216. The first series of inhibitors has a m-chlorobenzyl moiety binding in the S1 pocket, and the second has a benzamidine moiety. When the adjacent hydrogen bond is present, the enhanced binding affinity per A(2) of hydrophobic contact surface in the S3 pocket improves by 75% and 59%, respectively, over the inhibitors lacking this hydrogen bond. This improvement of the binding affinity per A(2) demonstrates cooperativity between the hydrophobic interaction and the hydrogen bond.

Theoretical study of the electronic spectrum of the CoH molecule

Calculated potential energy curves and spectroscopic parameters of the ground and various low‐lying excited states of the cobalt hydride molecule are presented. Over 30 electronic states of singlet, triplet, and quintet multiplicity have been obtained with adiabatic excitation energies below 4 eV. In addition, the electronic structure of several negative ion states has been determined. CoH− possesses a 4Φ electronic ground state and at least three other electronic states that are stable with respect to electron autodetachment. The calculations include relativistic effects variationally by employing a one‐component no‐pair operator with external‐field projectors. Electron correlation is accounted for by using multireference single and double excitation configuration interaction methods. Several experimentally observed bands in the optical spectrum of CoH are ascribed to transitions between the X 3Φ ground state and excited states of 3Φ, 3Δ, and 1Γ symmetry.

Energetics and Mechanism of the Hydrogenation of XHn for Group IV to Group VII Elements X.

High-level ab initio calculations of the NESC/SOC/CCSD(T)/cc-pV5Z type (NESC, Normalized Elimination of the Small Component; SOC, spin-orbit coupling corrections using the Breit-Pauli Hamiltonian) are employed to determine the energetics of the 18 hydrogenation reactions XHn + H2 → XHn+1 + H with X = F, Cl, Br, I, O, S, Se, Te, N, P, As, Sb, Bi, C, Si, Ge, Sn, and Pb. Accurate reaction and activation enthalpies as well as the corresponding free energies are obtained by calculating vibrational, thermochemical, and entropy corrections with a cc-pVTZ basis set. Also calculated are accurate X-H bond dissociation enthalpies at 298 K. The reaction mechanism of all 18 reactions is analyzed using the unified reaction valley approach (URVA) and UMP2/6-31G(d,p) to determine each reaction valley with high accuracy (step size 0.005 to 0.03 amu(1/2) bohr). By analyzing the reaction path curvature, the mechanism can be partitioned into four to six reaction phases, in which the reaction complex XHn···H2 undergoes specific chemical transformations. The fate of the reaction complex is determined at an early stage in the entrance channel. Curvature peaks reflect the strength of the bonds being broken or formed and provide the basis for a quantitative justification of the Hammond-Leffler postulate.

Combined QM/MM Study of Thyroid and Steroid Hormone Analogue Interactions with αvβ3 Integrin

Recent biochemical studies have identified a cell surface receptor for thyroid and steroid hormones that bind near the arginine-glycine-aspartate (RGD) recognition site on the heterodimeric αvβ3 integrin. To further characterize the intermolecular interactions for a series of hormone analogues, combined quantum mechanical and molecular mechanical (QM/MM) methods were used to calculate their interaction energies. All calculations were performed in the presence of either calcium (Ca2+) or magnesium (Mg2+) ions. These data reveal that 3,5′-triiodothyronine (T3) and 3,5,3′,5′-tetraiodothyroacetic acid (T4ac) bound in two different modes, occupying two alternate sites, one of which is along the Arg side chain of the RGD cyclic peptide site. These orientations differ from those of the other ligands whose alternate binding modes placed the ligands deeper within the RGD binding pocket. These observations are consistent with biological data that indicate the presence of two discrete binding sites that control distinct downstream signal transduction pathways for T3.

Solving the Pericyclic–Pseudopericyclic Puzzle in the Ring-Closure Reactions of 1,2,4,6-Heptatetraene Derivatives

The ongoing controversy whether cyclization reactions of conjugated allenes or ketenes follow a pericyclic or a pseudopericyclic mechanism has triggered dozens of investigations, which have led to new valuable synthetic routes. In this work, the mechanism of 10 representative cyclization reactions of hepta-1,2,4,6-tetraenes with different terminal groups is investigated utilizing the unified reaction valley approach that registers all electronic structure changes of the target molecule along the entire reaction pathway. A clear differentiation between a purely pericyclic and a purely pseudopericyclic mechanism is established. Additionally, it is found that, by using suitable functional groups, a pericyclic mechanism can be converted into a pseudopericyclic one, which is associated with a steady decrease of the reaction barrier and a continuous change from one mechanism to the other. The energetics of the reaction are confirmed by coupled cluster calculations of the CCSD(T) type. The mechanistic insight gained is used to design new pseudopericyclic reactions with low or no barrier, which will open new synthetic avenues.

Chiral Discrimination by Vibrational Spectroscopy Utilizing Local Modes

Chiral discrimination of homochiral and heterochiral H-bonded complexes is a challenge for both experimentalists and computational chemists. It is demonstrated that a two-pronged approach based on far-infrared vibrational spectroscopy and the calculation of local mode frequencies facilitates the chiral discrimination of H-bonded dimers. The local H-bond stretching frequencies identify the strongest H-bonds and by this the dominating chiral diastereomer. This is shown in the case of peroxide, trioxide, hydrazine, glycidol, and butan-2-ol dimers as well as propylene oxide···glycidol complexes investigated with the help of second-order Møller-Plesset perturbation, coupled cluster, and density functional theory calculations where, in the latter case, the ωB97X-D functional was used for an improved description of H-bonding. In some cases, additional intermolecular interactions overrule the important role of H-bonding, which is found by calculating chirodiastaltic energies.

A New Method for Describing the Mechanism of a Chemical Reaction Based on the Unified Reaction Valley Approach.

The unified reaction valley approach (URVA) used for a detailed mechanistic analysis of chemical reactions is improved in three different ways: (i) Direction and curvature of path are analyzed in terms of internal coordinate components that no longer depend on local vibrational modes. In this way, the path analysis is no longer sensitive to path instabilities associated with the occurrences of imaginary frequencies. (ii) The use of third order terms of the energy for a local description of the reaction valley allows an extension of the URVA analysis into the pre- and postchemical regions of the reaction path, which are typically characterized by flat energy regions. (iii) Configurational and conformational processes of the reaction complex are made transparent even in cases where these imply energy changes far less than a kcal/mol by exploiting the topology of the potential energy surface. As examples, the rhodium-catalyzed methanol carbonization, the Diels-Alder reaction between 1,3-butadiene and ethene, and the rearrangement of HCN to CNH are discussed.

The mechanism of the cycloaddition reaction of 1,3-dipole molecules with acetylene: an investigation with the unified reaction valley approach

The unified reaction valley approach (URVA) is used in connection with a dual-level approach to describe the mechanism of ten different cycloadditions of 1,3-dipoles XYZ (diazonium betaines, nitrilium betaines, azomethines, and nitryl hydride) to acetylene utilizing density functional theory for the URVA calculations and CCSD(T)-F12/aug-cc-pVTZ for the determination of the reaction energetics. The URVA results reveal that the mechanism of the 1,3-dipolar cycloadditions is determined early in the van der Waals range where the mutual orientation of the reactants (resulting from the shape of the enveloping exchange repulsion spheres, electrostatic attraction, and dispersion forces) decides on charge transfer, charge polarization, the formation of radicaloid centers, and the asynchronicity of bond formation. All cycloadditions investigated are driven by charge transfer to the acetylene LUMO irrespective of the electrophilic/nucleophilic character of the 1,3-dipole. However, an insufficient charge transfer typical of an electrophilic 1,3-dipole leads to a higher barrier. Energy transfer and energy dissipation as a result of curvature and Coriolis couplings between vibrational modes lead to an unusual energy exchange between just those bending modes that facilitate the formation of radicaloid centers. The relative magnitude of the reaction barriers and reaction energies is rationalized by determining reactant properties, which are responsible for the mutual polarization of the reactants and the stability of the bonds to be broken or formed.