Showing papers by "James Alexis Platts published in 2006"

Hybrid density functional theory for π-stacking interactions : application to benzenes, pyridines, and DNA bases

Abstract: The suitability of a hybrid density functional to qualitatively reproduce geometric and energetic details of parallel pi-stacked aromatic complexes is presented. The hybrid functional includes an ad hoc mixture of half the exact (HF) exchange with half of the uniform electron gas exchange, plus Lee, Yang, and Parr's expression for correlation energy. This functional, in combination with polarized, diffuse basis sets, gives a binding energy for the parallel-displaced benzene dimer in good agreement with the best available high-level calculations reported in the literature, and qualitatively reproduces the local MP2 potential energy surface of the parallel-displaced benzene dimer. This method was further critically compared to high-level calculations recently reported in the literature for a range of pi-stacked complexes, including monosubstituted benzene-benzene dimers, along with DNA and RNA bases, and generally agrees with MP2 and/or CCSD(T) results to within +/-2 kJ mol(-1). We also show that the resulting BH&H binding energy is closely related to the electron density in the intermolecular region. The net result is that the BH&H functional, presumably due to fortuitous cancellation of errors, provides a pragmatic, computationally efficient quantum mechanical tool for the study of large pi-stacked systems such as DNA.

Calculation of intermolecular interactions in the benzene dimer using coupled-cluster and local electron correlation methods

Abstract: Potential energy curves for the parallel-displaced, T-shaped and sandwich structures of the benzene dimer are computed with density fitted local second-order Moller–Plesset perturbation theory (DF-LMP2) as well as with the spin-component scaled (SCS) variant of DF-LMP2. While DF-LMP2 strongly overestimates the dispersion interaction, in common with canonical MP2, the DF-SCS-LMP2 interaction energies are in excellent agreement with the best available literature values along the entire potential energy curves. The DF-SCS-LMP2 dissociation energies for the three structures are also compared with new complete basis set estimates of the interaction energies obtained from accurate coupled cluster (CCSD(T)) and DF-SCS-MP2 calculations. Since LMP2 is essentially free of basis set superposition errors, counterpoise corrections are not required. As a result, DF-SCS-LMP2 is computationally inexpensive and represents an attractive method for the study of larger π-stacked systems such as truncated sections of DNA.

Four-membered group 13 metal(I) N-heterocyclic carbene analogues: Synthesis, characterization, and theoretical studies

Abstract: The synthesis, spectroscopic and structural characterization of the monomeric, four-membered group 13 metal(I) heterocycles ([:M{eta2-N,N'-(Ar)NC(NCy2)N(Ar)}], M = Ga or In, Ar = C6H3Pri2-2,6) and an isomeric thallium complex are reported. Theoretical studies on these complexes, which are analogues of four-membered N-heterocyclic carbenes, suggest they should act as good sigma-donor ligands.

A QM/MM Study of Cisplatin–DNA Oligonucleotides: From Simple Models to Realistic Systems

Abstract: QM/MM calculations were employed to investigate the role of hy- drogen bonding and p stacking in sev- eral single- and double-stranded cispla- tin-DNA structures. Computed geo- metrical parameters reproduce experi- mental structures of cisplatin and its complex with guanine-phosphate-gua- nine. Following QM/MM optimisation, single-point DFT calculations allowed estimation of intermolecular forces through atoms in molecules (AIM) analysis. Binding energies of platinated single-strand DNA qualitatively agree with myriad experimental and theoreti- cal studies showing that complexes of guanine are stronger than those of ade- nine. The topology of all studied com- plexes confirms that platination strong- ly affects the stability of both single- and double-stranded DNAs: Pt! N! H···X (X = N or O) interactions are ubiquitous in these complexes and ac- count for over 70% of all H-bonding interactions. The p stacking is greatly reduced by both mono- and bifunction- al complexation: the former causes a loss of about 3-4 kcalmol ! 1 , whereas the latter leads to more drastic disrup- tion. The effect of platination on Watson-Crick GC is similar to that found in previous studies: major redis- tribution of energy occurs, but the overall stability is barely affected. The BH&H/AMBER/AIM approach was also used to study platination of a double-stranded DNA octamer d(CCTG*G*TCC)·dA for which an experimental structure is available. Comparison between theory and experiment is satisfactory, and also reproduces previous DFT-based studies of analogous structures. The effect of platination is similar to that seen in model systems, although the effect on GC pairing was more pronounced. These calculations also reveal weaker, secondary interactions of the form Pt···O and Pt···N, detected in several single- and double-stranded DNA.

Gas-phase DNA oligonucleotide structures. A QM/MM and atoms in molecules study.

Abstract: QM/MM calculations have been employed to investigate the role of hydrogen bonding and π-stacking in single- and double-stranded DNA oligonucleotides. DFT calculations and Atoms in Molecules analysis on QM/MM-optimized structures allow characterization and estimation of the energies of π-stacking and hydrogen-bond interactions. This shows that π-stacking interactions depend on the number and the nature of the DNA bases for single-stranded nucleotides; for instance, guanines are found to be involved in strong hydrogen bonds, whereas adenines interact mainly via stacking interactions. The role of interbase hydrogen bonding was explored: the −NH2 groups of guanine, adenine, and cytosine participate in N−H···O and N−H···N interactions. These are much stronger in single-strand oligonucleotides, where the −NH2 groups are highly nonplanar. In double-stranded DNA, the strong base-pairing hydrogen bonds of complementary bases lead to more planar −NH2 groups, which tend to be involved in π-stacking interactions rat...

Computational study of iminium ion formation: effects of amine structure

Abstract: Density functional calculations are used to explore the formation of iminium ions from secondary amines and acrolein and the subsequent reactivity of the resulting iminium ions. After establishing a feasible profile for this reaction in simulated experimental conditions, we focus on the effect of variation in amine structure on calculated barriers. This analysis shows that incorporation of a heteroatom (N or O) in the α-position to the reactive amine results in significantly reduced energy barriers, as does an electron-withdrawing group (carbonyl or thiocarbonyl) in the β-position. Electron density analysis is used to monitor reactions at a detailed level, and to identify important intermolecular interactions at both minima and transition states. Barriers to reaction are linked to calculated proton affinities of secondary amines, suggesting that the relative ease of protonation–deprotonation of the amine is a key property of effective catalysts. Moreover, barriers for subsequent Diels–Alder reaction of iminium ions with cyclopentadiene are lower than for their formation, suggesting that formation may be the rate determining step in the catalytic cycle.

Comparison of proposed putative active conformations of myelin basic protein epitope 87-99 linear altered peptide ligands by spectroscopic and modelling studies: The role of positions 91 and 96 in T-cell receptor activation

Abstract: This work proposes a structural motif for the inhibition of experimental autoimmune encephalomyelitis (EAE) by the linear altered peptide ligands (APLs) [Ala91,96] MBP87-99 and [Arg91,Ala96] MBP87-99 of myelin basic protein. Molecular dynamics was applied to reveal distinct populations of EAE antagonist [Ala91,96] MBP87-99 in solution, in agreement with NOE data. The combination of the theoretical and experimental results led to the identification of a putative active conformation. This approach is of value as no crystallographic data is available for the APL-receptor complex. TCR contact residue Phe89 has an altered topology in the putative bioactive conformations of both APLs with respect to the native peptide, as found via crystallography; it is no longer prominent and solvent exposed. It is proposed that the antagonistic activity of the APLs is due to their binding to MHC, preventing the binding of self-myelin epitopes, with the absence of an immunologic response as the loss of some interactions with the TCR hinders activation of T-cells.

A putative bioactive conformation for the altered peptide ligand of myelin basic protein and inhibitor of experimental autoimmune encephalomyelitis [Arg91, Ala96] MBP87–99

Abstract: [Arg91, Ala96] MBP87–99 is an altered peptide ligand (APL) of myelin basic protein (MBP), shown to actively inhibit experimental autoimmune encephalomyelitis (EAE), which is studied as a model of multiple sclerosis (MS). The APL has been rationally designed by substituting two of the critical residues for recognition by the T-cell receptor. A conformational analysis of the APL has been sought using a combination of 2D NOESY nuclear magnetic resonance (NMR) experiments and detailed molecular dynamics (MD) calculations, in order to comprehend the stereoelectronic requirements for antagonistic activity, and to propose a putative bioactive conformation based on spatial proximities of the native peptide in the crystal structure. The proposed structure presents backbone similarity with the native peptide especially at the N-terminus, which is important for major histocompatibility complex (MHC) binding. Primary (Val87, Phe90) and secondary (Asn92, Ile93, Thr95) MHC anchors occupy the same region in space, whereas T-cell receptor (TCR) contacts (His88, Phe89) have different orientation between the two structures. A possible explanation, thus, of the antagonistic activity of the APL is that it binds to MHC, preventing the binding of myelin epitopes, but it fails to activate the TCR and hence to trigger the immunologic response. NMR experiments coupled with theoretical calculations are found to be in agreement with X-ray crystallography data and open an avenue for the design and synthesis of novel peptide restricted analogues as well as peptide mimetics that rises as an ultimate goal.

Novel properties from experimental charge densities: an application to the zwitterionic neurotransmitter taurine.

Abstract: The charge distribution of taurine (2-aminoethane-sulfonic acid) is revisited by using an orbital-based method that describes the density in a fixed molecular orbital basis with variable orbital occupation numbers. A new neutron data set is also employed to explore whether this improves the deconvolution of thermal motion and charge density. A range of molecular properties that are novel for experimentally determined charge densities are computed, including Weinhold population analysis, Mayer bond orders, and local kinetic energy densities, in addition to charge topological analysis and quantum theory of atoms-in-molecules (QTAIM) integrated properties. The ease with which a distributed multipole analysis can be performed on the fitted density matrix makes it straightforward to compute molecular moments, the lattice energy, and the electrostatic interaction energies of molecules removed from the crystal. Results are compared with high-level (QCISD) gas-phase calculations and band structure calculations employing density functional theory. Finally, the avenues available for extending the range of molecular properties that can be calculated from experimental charge densities still further using this approach are discussed.

Quantum-Chemical Design of Cryptand-like Ditopic Salt Binders.

Abstract: Hartree-Fock, density functional, and MP2 methods are applied to the problem of designing neutral, bicyclic C3-symmetric cages incorporating interacting anion- and cation-binding sites which strongly bind NaCl as an ion contact pair. A large number of trial ligands L and their complexes L:NaCl are tested, with the focus on maximizing binding by (i) optimizing the cavity size and shape and (ii) varying the nature of the anion- and cation-binding functionalities. The corresponding complexes L:Cl(-) and L:Na(+) are also studied in some detail. An analysis of their structures and charge distributions helps to build a consistent picture of the requirements for a successful NaCl binding. The 'best' candidate ligand utilizes a tripodal triether-substituted amine N(CH2CH2OR-)3 to bind the sodium cation; three thiourea groups in a tripodal arrangement with a 1,3,5-trisubstituted benzyl spacer group {C6H3(CH2NHC [Formula: see text] XNH-)3 X=O,S} to bind chloride; and a -CH2CH2- spacer linking the two binding sites. A simple Quantitative Structure-Property analysis suggests that the binding cavity shape and size is near to the optimal one for this system.