•Computational methods used to explore effects of ligand L on L-Pt-Amyloid-β conformers.•Ligands restrict peptide flexibility and affect the identity of Histidine binding sites.•Each ligand affects peptide secondary structure to a markedly different degree.Ligand field molecular mechanics (LFMM) and semi-empirical Parametric Model 7 (PM7) methods are applied to a series of six PtII-Ligand systems binding to the N-terminal domain of the amyloid-β (Aβ) peptide. Molecular dynamics using a combined LFMM/Assisted Model Building with Energy Refinement (AMBER) approach is used to explore the conformational freedom of the peptide fragment, and identifies favourable platinum binding modes and peptide conformations for each ligand investigated. Platinum coordination is found to depend on the nature of the ligand, providing evidence that binding mode may be controlled by suitable ligand design. Boltzmann populations at 310 K indicate that each Pt-Aβ complex has a small number of thermodynamically accessible states. Ramachandran maps are constructed for the sampled Pt-Aβ conformations and secondary structural analysis of the obtained complex structures is performed and contrasted with the free peptide; coordination of these platinum complexes disrupts existing secondary structure in the Aβ peptide and promotes formation of ligand-specific turn-type secondary structure.A combination of ligand field molecular mechanics and semi-empirical methods are used to examine how ligand choice affects the coordination of Pt(II) to models of amyloid-β peptides.Download high-res image (151KB)Download full-size image

Ligand field molecular mechanics (LFMM), density functional theory (DFT), and semiempirical PM7 methods are used to study the binding of two Pt(II)-L systems to an N-terminal fragment of the amyloid-β peptide, where L = 2,2-bipyridyl or 1,10-phenanthroline. Molecular dynamics simulations are used to explore the conformational freedom of the peptide using LFMM combined with AMBER molecular mechanics parameters. We establish a modeling protocol, allowing for identification and analysis of favorable platinum-binding modes and peptide conformations. Preferred binding modes are identified for each ligand investigated; metal coordination occurs via Nε in His residues for both ligands - His6ε-His13ε and His6ε-His14ε for the bipyridyl and phenanthroline ligands, respectively. The observed change in binding mode for the different ligands suggests that the binding mode of these platinum-based structures can be controlled by the choice of ligand. In the bipy systems, Boltzmann population at 310 K is dominated by a single conformer, while in the phenanthroline case, three conformations make significant contributions to the ensemble. The relative stability of these conformations is due to the inherent stability of binding platinum via Nε in addition to subtle H-bonding effects.

Structural properties such as size, shape and density distribution of a range of N-(2-hydroxypropyl)methacrylamide (HPMA) polymers in various solvent models have been investigated. Common atomistic force fields were compared against rotational barriers and relative conformational energies obtained from ab initio and density functional theory (DFT) data for a monomer and dimer of HPMA. This identified the AMBER99 parameter set as the most appropriate for representing the structures and so AMBER99 was employed for all molecular dynamics simulations. MD trajectories were calculated for a range of polymer sizes from 4 to 265 repeat units (2 to 35 kDa). The time averaged radius of gyration was extracted from trajectories and interpreted in the context of Flory's mean field approach. Comparison with data obtained from small angle neutron scattering (SANS) experiments was then used to differentiate between alternative solvent models. The shape adopted by such polymers was evaluated by fitting structures to ellipsoids, to allow separate analysis of radius and density profile along each axis. The density distribution of atoms was defined using these ellipsoids according to centre of mass or centre of neutron scattering lengths, the latter allowing direct comparison with experimental SANS data. We show that computational simulation of such polymers has practical application in obtaining detailed morphological information of polymer solution structure, and as a benchmark for coarse-grained methods.

We report the performance of composite post-MP2 ab initio methods with small basis sets for description of noncovalent interactions, using the S66 data set as a benchmark. For three representative complexes, it is shown that explicitly correlated coupled cluster (CCSD-F12a) methods yield interaction energies ca. 0.1 kcal/mol from the complete basis set limit with aug-cc-pVDZ. Triple excitations are not explicitly correlated in this approach, but we show that scaling the perturbative triples via the (T*) approximation improves agreement with benchmark values. Across the entire S66 data set, this approach results in a root-mean-square error (RMSE) of 0.13 kcal/mol or 3%, with well-balanced description of all classes of complex. The basis set dependence of traditional CCSD(T) interaction energies is examined, and the small 6-31G*(0.25) basis set is found to give particularly accurate results (RMSE = 0.15 kcal/mol, or 4%). We also employ spin component scaling (SCS) of CCSD-F12a data, which gives slightly better accuracy than CCSD(T*)-F12a if contributions from same- and opposite-spin pairs are optimized for this data set (RMSE = 0.08 kcal/mol, or 2%). Interpolation of local MP2 and MP3 is also shown to accurately reproduce benchmark data with both aug-cc-pVDZ (RMSE = 0.18 kcal/mol or 5%) and 6-31G*(0.25) (RMSE = 0.13 kcal/mol or 4%).

Hybrid QM/MM calculations on adducts of five platinum-based anti-cancer drugs, namely cisplatin, oxaliplatin, lobaplatin, and heptaplatin are reported. Starting from the NMR structure of a cisplatin–DNA octamer complex (PDB entry 1AU5), we compare DNA binding of drugs that differ in their carrier ligands, and hence in their potential interactions with DNA. It is shown that all drugs induce broadly similar changes to the regular helical structure of DNA, but that variations in ligand lead to subtle differences in complex geometry, with cisplatin exhibiting notably different properties to other drugs. Cisplatin is also the most weakly bound of drugs considered here, and heptaplatin the most strongly bound. Differences in binding appear to be due to changes in the pattern of non-covalent interactions between drug and DNA, especially hydrogen bonding to oxygen in guanine and phosphate groups. Despite adopting very similar geometries, two isomers of lobaplatin (RRS and SSS) are found to have quite different binding energies, the latter being bound by up to 30 kcal mol−1 more than the former.

Zirconium and hafnium metallocene dihalides based on simple polyphenyl cyclopentadienes are stable room-temperature lumophores with large Stokes shifts, emitting from states with substantial LMCT character. Their synthesis is described, including by a rapid solvent-free approach compatible with the lifetime of PET-active isotopes (89Zr). Preliminary experiments indicate the viability of these species as lumophores for fluorescence cell-imaging microscopy.

Ab initio and density functional theory (DFT) calculations on some model systems are presented to assess the extent to which intermolecular hydrogen bonding can affect the planarity of amide groups. Formamide and urea are examined as archetypes of planar and non-planar amides, respectively. DFT optimisations suggest that appropriately disposed hydrogen-bond donor or acceptor molecules can induce non-planarity in formamide, with OCNH dihedral angles deviating by up to ca. 20° from planarity. Ab initio energy calculations demonstrate that the energy required to deform an amide molecule from the preferred geometry of the isolated molecule is more than compensated by the stabilisation due to hydrogen bonding. Similarly, the NH2 group in urea can be made effectively planar by the presence of appropriately positioned hydrogen-bond acceptors, whereas hydrogen-bond donors increase the non-planarity of the NH2 group. Small clusters (a dimer, two trimers and a pentamer) extracted from the crystal structure of urea indicate that the crystal field acts to force planarity of the urea molecule; however, the interaction with nearest neighbours alone is insufficient to induce the molecule to become completely planar, and longer-range effects are required. Finally, the potential for intermolecular hydrogen bonding to induce non-planarity in a model of a peptide is explored. Inter alia, the insights obtained in the present work on the extent to which the geometry of amide groups may be deformed under the influence of intermolecular hydrogen bonding provide structural guidelines that can assist the interpretation of the geometries of such groups in structure determination from powder X-ray diffraction data.

A violet-blue cobalt(II) complex [Co(4-nbz)2(DMP)2] (1), where 4-nbz = 4-nitrobenzoate and DMP = 3,5-dimethylpyrazole, has been prepared at room temperature. Crystallographic studies on 1·0.5H2O reveal that the molecules of 1 are linked by a variety of non-covalent bonds including a novel type of C–H⋯C contact forming, with assistance from N–H⋯O, C–H⋯O and C–H⋯π interactions, an intricate 3-D supramolecular network. Theoretical calculations suggest that the observed C–H⋯C interactions are energetically quite significant.

Comparison of the relative reactivities of the benchmark catalysts for iminium ion catalysed Diels–Alder cycloaddition under optimised literature conditions showed the imidazolidinone scaffold to possess significantly superior levels of activity in the Diels–Alder cycloaddition when compared to diarylprolinol silyl ethers.

Density functional theory (DFT) calculations have been performed to determine the strength and geometry of intermolecular interactions of “piano-stool” ruthenium arene complexes, which show potential as anticancer treatments. Model complexes with methane and benzene indicate that the coordinated arene has C–H···π acceptor ability similar to that of free benzene, whereas this arene acts as a much stronger C–H donor or partner in π-stacking than free benzene. The source of these enhanced interactions is identified as a combination of electrostatic and dispersion effects. Complexes of Ru-arene complexes with base-pair step fragments of DNA, in which the arene has the potential to act as an intercalator, have also been investigated. Binding energies are found to be sensitive to the size and nature of the arene, with larger and more flexible arenes having stronger binding. π-stacking and C–H···π interactions between arene and DNA bases and hydrogen bonds from coordinated N–H to DNA oxygen atoms, as well as covalent Ru–N bonding, contribute to the overall binding. The effect of complexation on DNA structure is also examined, with larger rise and more negative slide values than canonical B-DNA observed in all cases.

High-resolution X-ray diffraction data, coupled with theoretical calculations, are used to demonstrate the presence of a non-nuclear local maximum in the electron density of a dimeric Mg(I) molecule. This is the first time such a non-nuclear attractor (NNA) has been observed in a stable molecular species. Multipole modeling of the Mg(I) centers requires use of expansion/contraction (κ) coefficients taken from density functional theory (DFT), since accurate scattering factors for Mg(I) are not available. The model developed accurately accounts for the electron density in the Mg−Mg region and is in excellent agreement with directly calculated DFT data. Within the quantum theory of atoms in molecules (QTAIM), this molecule is not bound by a Mg−Mg bond but rather by two Mg−“pseudo-atom” bonds. The NNA is associated with a large region of negative Laplacian in the Mg−Mg internuclear region and arises from the overlap of 3s orbitals in this long, nonpolar “bond”. The pseudoatomic basin associated with the NNA contains 0.8 electrons, which are highly delocalized and hence weakly bound. Possible implications of this unusual electronic structure for the chemistry of such molecules, including their use as excellent reducing agents, are discussed.

Prediction of the binding energy of a peptide implicated in multipole sclerosis to its major histocompatibility complex (MHC) receptor is reported using numerous ab initio, density functional (DFT) and semi-empirical theoretical methods. Using the crystalline coordinates taken from the protein databank, two ab initio methods are shown to be in good agreement for pairwise interaction of amino acids. These data are then used to benchmark more approximate DFT and semi-empirical approaches, which are shown to have substantial errors. However, in some cases significant improvement is apparent on inclusion of an empirical correction to account for dispersion interactions. Most promising among these cases is RM1, a re-parameterisation of the popular AM1 method for atoms typically found in organic and biological molecules. Together with the dispersion correction, this reproduces ab initio data with a mean unsigned error of 1.36 kcal/mol. This approach is used to predict binding for progressively larger model systems, up to binding of the peptide with the entire MHC receptor, and is then applied to multiple snapshots taken from molecular dynamics simulation.

Ab initio and density functional theory (DFT) calculations of nuclear magnetic resonance shielding tensors in benzene–methane and two isomers of the benzene dimer are reported, with the aim of probing the changes in shielding induced by the formation of supramolecular complexes from isolated molecules. It is shown that the changes in shielding (and hence of chemical shift) for hydrogen nuclei are broadly in line with expectations from “shielding cones” based on aromatic ring current, but that changes for carbon nuclei are rather more subtle. More detailed analysis indicates that the change in isotropic shielding results from much larger changes in individual components of the shielding tensor and in diamagnetic/paramagnetic shielding contributions. Benchmark data were obtained using Møller–Plesset 2nd order perturbation theory with a medium-sized basis set, but it is shown that Hartree–Fock and most density functional theory methods reproduce all essential changes in shielding, and do so in a reasonably basis set independent fashion. The chosen method is then applied to a DNA–intercalator complex.

This work reports molecular dynamics studies at the receptor level of the immunodominant myelin basic protein (MBP) epitope 87–99 implicated in multiple sclerosis, and its antagonists altered peptide ligands (APLs), namely [Arg91, Ala96] MBP87–99 and [Ala91,96] MBP87–99. The interaction of each peptide ligand with the receptor human leukocyte antigen HLA-DR2b was studied, starting from X-ray structure with pdb code: 1ymm. This is the first such study of APL-HLA-DR2b complexes, and hence the first attempt to gain a better understanding of the molecular recognition mechanisms that underlie TCR antagonism by these APLs. The amino acids His88 and Phe89 serve as T-cell receptor (TCR) anchors in the formation of the trimolecular complex TCR-peptide-HLA-DR2b, where the TCR binds in a diagonal, off-centered mode to the peptide-HLA complex. The present findings indicate that these two amino acids have a different orientation in the APLs [Arg91, Ala96] MBP87–99 and [Ala91,96] MBP87–99: His88 and Phe89 remain buried in HLA grooves and are not available for interaction with the TCR. We propose that this different topology could provide a possible mechanism of action for TCR antagonism.

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.

High level ab initio calculations on complexes of benzene with acrolein and ethene reveal that π⋯π interactions to electron deficient acrolein are remarkably similar to those found in the benzene dimer.

A violet-blue cobalt(II) complex [Co(4-nbz)2(DMP)2] (1), where 4-nbz = 4-nitrobenzoate and DMP = 3,5-dimethylpyrazole, has been prepared at room temperature. Crystallographic studies on 1·0.5H2O reveal that the molecules of 1 are linked by a variety of non-covalent bonds including a novel type of C–H⋯C contact forming, with assistance from N–H⋯O, C–H⋯O and C–H⋯π interactions, an intricate 3-D supramolecular network. Theoretical calculations suggest that the observed C–H⋯C interactions are energetically quite significant.

Ab initio and density functional theory (DFT) calculations of nuclear magnetic resonance shielding tensors in benzene–methane and two isomers of the benzene dimer are reported, with the aim of probing the changes in shielding induced by the formation of supramolecular complexes from isolated molecules. It is shown that the changes in shielding (and hence of chemical shift) for hydrogen nuclei are broadly in line with expectations from “shielding cones” based on aromatic ring current, but that changes for carbon nuclei are rather more subtle. More detailed analysis indicates that the change in isotropic shielding results from much larger changes in individual components of the shielding tensor and in diamagnetic/paramagnetic shielding contributions. Benchmark data were obtained using Møller–Plesset 2nd order perturbation theory with a medium-sized basis set, but it is shown that Hartree–Fock and most density functional theory methods reproduce all essential changes in shielding, and do so in a reasonably basis set independent fashion. The chosen method is then applied to a DNA–intercalator complex.

Ab initio and density functional theory (DFT) calculations on some model systems are presented to assess the extent to which intermolecular hydrogen bonding can affect the planarity of amide groups. Formamide and urea are examined as archetypes of planar and non-planar amides, respectively. DFT optimisations suggest that appropriately disposed hydrogen-bond donor or acceptor molecules can induce non-planarity in formamide, with OCNH dihedral angles deviating by up to ca. 20° from planarity. Ab initio energy calculations demonstrate that the energy required to deform an amide molecule from the preferred geometry of the isolated molecule is more than compensated by the stabilisation due to hydrogen bonding. Similarly, the NH2 group in urea can be made effectively planar by the presence of appropriately positioned hydrogen-bond acceptors, whereas hydrogen-bond donors increase the non-planarity of the NH2 group. Small clusters (a dimer, two trimers and a pentamer) extracted from the crystal structure of urea indicate that the crystal field acts to force planarity of the urea molecule; however, the interaction with nearest neighbours alone is insufficient to induce the molecule to become completely planar, and longer-range effects are required. Finally, the potential for intermolecular hydrogen bonding to induce non-planarity in a model of a peptide is explored. Inter alia, the insights obtained in the present work on the extent to which the geometry of amide groups may be deformed under the influence of intermolecular hydrogen bonding provide structural guidelines that can assist the interpretation of the geometries of such groups in structure determination from powder X-ray diffraction data.