Anthony K. Rappé

PI -STACKING INTERACTIONS : ALIVE AND WELL IN PROTEINS

A representative set of high resolution x-ray crystal structures of nonhomologous proteins have been examined to determine the preferred positions and orientations of noncovalent interactions between the aromatic side chains of the amino acids phenylalanine, tyrosine, histidine, and tryptophan. To study the primary interactions between aromatic amino acids, care has been taken to examine only isolated pairs (dimers) of amino acids because trimers and higher order clusters of aromatic amino acids behave differently than their dimer counterparts. We find that pairs (dimers) of aromatic side chain amino acids preferentially align their respective aromatic rings in an off-centered parallel orientation. Further, we find that this parallel-displaced structure is 0.5–0.75 kcal/mol more stable than a T-shaped structure for phenylalanine interactions and 1 kcal/mol more stable than a T-shaped structure for the full set of aromatic side chain amino acids. This experimentally determined structure and energy difference is consistent with ab initio and molecular mechanics calculations of benzene dimer, however, the results are not in agreement with previously published analyses of aromatic amino acids in proteins. The preferred orientation is referred to as parallel displaced π-stacking.

Methanation of CO over Ni catalyst: A theoretical study*

Theoretical methods (generalized valence‐bond calculations) were used to examine the bond energies and geometries of numerous species chemisorbed onto Ni clusters representing Ni surface. These results were used to obtain thermochemical information and to examine various mechanisms for the methanation of CO over Ni: CO+3H^(→)_(2(Ni)) CH_4+H_2O. It is found that chemisorbed formyl radicals (Ni–CHO) lead to a favorably appearing chain reaction that is consistent with current experimental results. In addition, we find a chemisorbed C_2 species that may be the catalytically active C_(ad) formed from dissociation of CO.

Scalable Anisotropic Shape and Electrostatic Models for Biological Bromine Halogen Bonds.

Halogens are important substituents of many drugs and secondary metabolites, but the structural and thermodynamic properties of their interactions are not properly treated by current molecular modeling and docking methods that assign simple isotropic point charges to atoms. Halogen bonds, for example, are becoming widely recognized as important for conferring specificity in protein-ligand complexes but, to this point, are most accurately described quantum mechanically. Thus, there is a need to develop methods to both accurately and efficiently model the energies and geometries of halogen interactions in biomolecular complexes. We present here a set of potential energy functions that, based on fundamental physical properties of halogens, properly model the anisotropic structure-energy relationships observed for halogen interactions from crystallographic and calorimetric data, and from ab initio calculations for bromine halogen bonds in a biological context. These energy functions indicate that electrostatics alone cannot account for the very short-range distances of bromine halogen bonds but require a flattening of the effective van der Waals radius that can be modeled through an angular dependence of the steric repulsion term of the standard Lennard-Jones type potential. This same function that describes the aspherical shape of the bromine is subsequently applied to model the charge distribution across the surface of the halogen, resulting in a force field that uniquely treats both the shape and electrostatic charge parameters of halogens anisotropically. Finally, the electrostatic potential was shown to have a distance dependence that is consistent with a charge-dipole rather than a simple Coulombic type interaction. The resulting force field for biological halogen bonds (ffBXB) is shown to accurately model the geometry-energy relationships of bromine interactions to both anionic and neutral oxygen acceptors and is shown to be tunable by simply scaling the electrostatic component to account for effects of varying electron-withdrawing substituents (as reflected in their Hammett constants) on the degree of polarization of the bromine. This approach has broad applications to modeling the structure-energy relationships of halogen interactions, including the rational design of inhibitors against therapeutic targets.

Uncovering the Roles of Oxygen in Cr(III) Photoredox Catalysis

A combined experimental and theoretical investigation aims to elucidate the necessary roles of oxygen in photoredox catalysis of radical cation based Diels-Alder cycloadditions mediated by the first-row transition metal complex [Cr(Ph2phen)3](3+), where Ph2phen = bathophenanthroline. We employ a diverse array of techniques, including catalysis screening, electrochemistry, time-resolved spectroscopy, and computational analyses of reaction thermodynamics. Our key finding is that oxygen acts as a renewable energy and electron shuttle following photoexcitation of the Cr(III) catalyst. First, oxygen quenches the excited Cr(3+)* complex; this energy transfer process protects the catalyst from decomposition while preserving a synthetically useful 13 μs excited state and produces singlet oxygen. Second, singlet oxygen returns the reduced catalyst to the Cr(III) ground state, forming superoxide. Third, the superoxide species reduces the Diels-Alder cycloadduct radical cation to the final product and reforms oxygen. We compare the results of these studies with those from cycloadditions mediated by related Ru(II)-containing complexes and find that the distinct reaction pathways are likely part of a unified mechanistic framework where the photophysical and photochemical properties of the catalyst species lead to oxygen-mediated photocatalysis for the Cr-containing complex but radical chain initiation for the Ru congener. These results provide insight into how oxygen can participate as a sustainable reagent in photocatalysis.

Force Field Model of Periodic Trends in Biomolecular Halogen Bonds

The study of the noncovalent interaction now defined as a halogen bond (X-bond) has become one of the fastest growing areas in experimental and theoretical chemistry--its applications as a design tool are highly extensive. The significance of the interaction in biology has only recently been recognized, but has now become important in medicinal chemistry. We had previously derived a set of empirical potential energy functions to model the structure-energy relationships for bromines in biomolecular X-bonds (BXBs). Here, we have extended this force field for BXBs (ffBXB) to the halogens (Cl, Br, and I) that are commonly seen to form stable X-bonds. The ffBXB calculated energies show a remarkable one-to-one linear relationship to explicit BXB energies determined from an experimental DNA junction system, thereby validating the approach and the model. The resulting parameters allow us to interpret the stabilizing effects of BXBs in terms of well-defined physical properties of the halogen atoms, including their size, shape, and charge, showing periodic trends that are predictable along the Group VII column of elements. Consequently, we have established the ffBXB as an accurate computational tool that can be applied, for example, for the design of new therapeutic compounds against clinically important targets and new biomolecular-based materials.

van der Waals functional forms for molecular simulations

We derive the general functional form for the van der Waals interaction of two 1s orbitals without resorting to approximating the interaction Hamiltonian by a power series expansion. We find the functional form to be the difference between two Extended Rydberg functions. The Morse function offers a good approximation for it. Reference potentials for several small systems are fit with the Morse, exponential‐6, and Lennard‐Jones functional forms. The Morse functional form describes nonbonded interactions quite well, while the more conventional functional forms possess the wrong shape.

Rff, Conceptual Development of a Full Periodic Table Force Field for Studying Reaction Potential Surfaces

The attributes of a general molecular mechanics force field needed for the study of chemical reactions are described. This attribute set is referred to as a reaction force field (RFF). The functional forms of a first generation reaction force field, RFF1, are presented along with illustrative transition state geometries, activation energies, and reaction coordinate imaginary frequencies.

Theoretical characterization of deNOx catalysis: The initial nitrogen coupling step

Abstract The microscopic steps involved in the formation of nitrous oxide from two nitric oxides with an Fe(II) catalyst are discussed in the context of an ab initio theoretical study. We find the coupled products energetically accessible given an appropriate ligand backbone (two waters of hydration). Specifically, we find the dinitrogen dioxide cognate 24 kcal/mol below the dinitrosyl reactant FeCl 2 (NO) 2 (H 2 O) 2 and the cis -hyponitrite isomer only 4 kcal/mol above the dinitrosyl. Further, an orbital correlation diagram is used to assert that the proposed intermediates are kinetically accessible as well. Finally, we utilize the correlation diagram to suggest that the proposed process is kinetically viable for group VI through VIII metal dications.

Molecular mechanics studies of coenzyme B12 complexes with constrained CoN(axial-base) bond lengths: introduction of the universal force field (UFF) to coenzyme B12 chemistry and its use to probe the plausibility of an axial-base-induced, ground-state corrin butterfly conformational steric effect

Abstract The universal force field (UFF) is used to minimize a series of cobalamins to (i) test the applicability of UFF to model unstrained cobalamin structures in comparison with the literature force field MM2′, a force field parameterized using a set of 19 cobalamin X-ray crystal structures, and (ii) to probe the steric-based, ground-state corrin butterfly effect, a literature hypothesis aimed at explaining the observed 10 12 enzymic acceleration of adenosylcobalamin (AdoCbl) CoC bond homolysis. The results obtained show that UFF is at least as good as MM2′ in modeling the five cobalamins which were originally used to test the accuracy of MM2′. Next, by using UFF to constrain the CoN(bzm) bond length in adenosylcobalamin (AdoCbl) to bond lengths ranging from 4.5 to 1.44 A, the putative axial-base-induced corrin butterfly conformation effect was modeled. The results show that while a short CoN(bzm) bond length does lengthen the CoC bond and increase the CoCC bond angle, the maximum magnitude of the predicted distortions appears, at least when considering steric effects alone, to be at most ∼1/3 that needed to accomplish the observed CoC bond homolysis acceleration. Equivalent results were obtained in analogous studies of base-free adenosylcobinamide (AdoCbi + ) in the presence of an exogenous N -methylimidazole base, [AdoCbi·N-MeIm] + . Overall, literature precedent, and now UFF molecular mechanics, all provide evidence against a solely axial-base-driven, sterically-induced corrin butterfly conformation effect as the dominant mechanism in the enzymic acceleration of AdoCbl CoC bond homolysis. Serious consideration must now be given to a combination of effects: an enzyme-induced rack mechanism (which can contain an enzyme -induced corrin butterfly conformational effect), and a coupling of Co⋯C cleavage, substrate or cysteine S⋯H bond cleavage, and Ado⋯H bond formation steps.

APT a next generation QM-based reactive force field model

Modelling reactivity at the nanoscale is a major computational challenge. Both reactive force field and combined QM–MM methodologies have been and are being developed to study reactivity at this boundary between molecules and the solid state. There have been more than 1500 publications since the mid-1990s, on combined QM–MM methodologies. Limitations in current models include the distortional characteristics of force field potential terms, the smooth transit from one potential surface to another, rather than surface hopping, and the blending of electrostatics between QM and MM portions of a QM–MM model. Functional forms, potential surface coupling terms, and parameterization strategies for the Approximate Pair Theory (APT), a next generation reactive force field model, are described. The APT model has been developed to correct a number of limitations in current reactive force field models as well as providing a foundation for a next generation QM–MM model. Chemical bonding concepts are used to develop fully dissociative bond stretch, bend, torsion, and inversion valence terms. Quantum mechanics also provides functional forms for potential surface coupling terms that permit a general description of reactivity from hydrogen bonding, through non-classical carbocations and cracking, to olefin polymerization, oxidation, and metathesis. Van der Waals, electrostatic, and metallic bonding models also derive from quantum mechanical resonance. Finally, Pauli Principle-based orthogonality provides a way to electrostatically couple the QM and MM portions of a QM–MM model that will support arbitrarily large basis sets.