Rendering of quantum topological atoms and bonds

BROWN:BIOISOSTERES MED CH O-BK, 2012

The design and application of bioisosteres is a core aspect of drug design that is practiced widely by medicinal chemists either overt or subliminally. As a neophyte in the pharmaceutical industry, I recall being fascinated by the concept of bioisosterism, an interest that was strongly fueled by Thornbers 1979 review [1] that I discovered early in my career and that stimulated a lifelong interest in this design principle. As an aspiring medicinal chemist, I found this review to be an important and useful resource that readily allowed me to contemplate biological metaphors by the simple act of reviewing the structural similes cataloged in a graphical fashion. Although preceding the discovery of Thornbers article, my first successful experience with the design of biologically active inhibitors relied upon bioisosterism as the underlying concept. I was charged with the task of identifying structurally distinct inhibitors of the low K m cAMP phosphodiesterase III isozyme based on 3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-ones, a chemotype that was discovered and developed at Bristol Laboratories [2]. Anagrelide (1) was the prototype of a series of potent inhibitors of blood platelet aggregation that, unfortunately, also caused thrombocytopenia, a reduction in platelet count that prevented further development of the compound as an antithrombotic agent. However, this aspect of the pharmacology of anagrelide led to its ultimate marketing as a therapeutic for the treatment for polycythemia vera, an overproduction of blood platelets that upsets the delicate balance of blood flow and clot formation and that predisposes afflicted individuals to thrombotic events. Preclinical species were unable to recapitulate the effect of anagrelide on platelet count, precipitating the view that if this phenomenon were related to the structure of the compound, an alternative heterocyclic core would increase the potential to avoid thrombocytopenia. A topological rearrangement of the N and C atoms on the lower edge of the molecule led to a series 1H-imidazo[4,5-b]quinolin-2(3H)-one derivatives that had been explored in only a very cursory fashion in the literature with examples restricted to essentially the parent compound. This class Bioisosteres in Medicinal Chemistry, First Edition. Edited by Nathan Brown

We show that the mutual, through-space compression of atomic volume experienced by approaching topological atoms causes an exponential increase in the intra-atomic energy of those atoms, regardless of approach orientation. This insight was obtained using the modern energy partitioning method called interacting quantum atoms (IQA). This behaviour is consistent for all atoms except hydrogen, which can behave differently depending on its environment. Whilst all atoms experience charge transfer when they interact, the intra-atomic energy of the hydrogen atom is more vulnerable to these changes than larger atoms. The difference in behaviour is found to be due to hydrogen's lack of a core of electrons, which, in heavier atoms, consistently provide repulsion when compressed. As such, hydrogen atoms do not always provide steric hindrance. In accounting for hydrogen's unusual behaviour and demonstrating the exponential character of the intra-atomic energy in all other atoms, we provide evidence for IQA's intraatomic energy as a quantitative description of steric energy.

Synthesis and Reactivity in Inorganic Metal-Organic and Nano-Metal Chemistry, 2008

Water undergoes important electrostatic changes within clusters and the liquid phase, in particular the enhancement of the dipole moment of a central water molecule. We systematically investigate the effect that increasing cluster size (up to 21‐mer) has on the dipole and quadrupole moments of a water molecule located at the centre of a cluster. Using hundreds of clusters, sampled from a Molecular Dynamics simulation, molecular multipole moments are reconstructed from the atomic multipole moments. These atomic multipole ...

Physical chemistry chemical physics : PCCP, 2016

An interaction between two atoms, bonded or non-bonded, consists of interatomic contributions: electrostatic energy, exchange energy and electronic correlation energy. Together with the intra-atomic energy of an atom, these contributions are the basic components of the Interacting Quantum Atom (IQA) energy decomposition scheme. Here, we investigate IQA's proper use in conjunction with an explicit implementation of the B3LYP functional. The recovery of the total molecular energy from the IQA components is emphasised, for the first time. A systematic study of three model systems of biological relevance, N-methylacetamide (NMA), the doubly capped tripeptide GlyGlyGly and an alloxan dimer, shows the stabilization effect of B3LYP on most of the interatomic exchange energies (V) compared to their Hartree-Fock values. Diagrams of exchange energies versus interatomic distance show the clustering of interactions, one cluster for each 1,n (n = 1 to 6 where the atoms are separated by n - 1...

Structural Chemistry, 2017

Here, we extend the system energy prediction approach used in the force field FFLUX (Maxwell et al. Theor Chem Acc 135:195, 2016) to complexes bound by weak intermolecular interactions. The investigation features the first application of the approach to bound complex systems, additionally challenged by investigating complexes held together only weakly, through either a predominant dispersion contribution, or through mixed dispersion and hydrogen-bonding. Our approach uses the interacting quantum atoms (IQA) energy partitioning scheme to obtain the intra-atomic, E A intra , and interatomic, V AA 0 inter , energies, which when summed, compose the molecular energy, E system IQA. The E A intra and V AA 0 inter energies are mapped to the positions of the nuclear coordinates through the machine learning method kriging to build atomic energy models. A model's quality is established through its ability to accurately predict the atomic and molecular energies of atoms in an external test set. Mean absolute error percentages (MAE%) of 1.5, 1.5, 1.6, 1.0, 2.6 and 1.7% are obtained in recovering the molecular energy for ammonia…benzene, wa-ter…benzene, HCN…benzene, methane…benzene, stackedbenzene (C 2h) dimer and T-benzene (C 2v) dimer complexes, respectively.

Theoretical Chemistry Accounts, 2016

Molecular Simulation, 2018

The optimisation of a peptide-capped glycine using the novel force field FFLUX is presented. FFLUX is a force field based on the machine-learning method kriging and the topological energy partitioning method called Interacting Quantum Atoms. FFLUX has a completely different architecture to that of traditional force fields, avoiding (harmonic) potentials for bonded, valence and torsion angles. In this study, FFLUX performs an optimisation on a glycine molecule and successfully recovers the target density-functionaltheory energy with an error of 0.89 ± 0.03 kJ mol −1. It also recovers the structure of the global minimum with a root-mean-squared deviation of 0.05 Å (excluding hydrogen atoms). We also show that the geometry of the intra-molecular hydrogen bond in glycine is recovered accurately.

Theoretical Chemistry Accounts, 2017

publication dimer). Although applied only for the water dimer in this work, the method is general and able to explain the gauche effect, the torsional barrier in biphenyl, the arrow-pushing scheme of an enzymatic reaction (peptide hydrolysis in the HIV-1 Protease active site), and halogen-alkane nucleophilic substitution (S N 2) reactions. Those applications will appear elsewhere as separate and elaborated case studies; here we focus on the details of the ANANKE method and its justification, using the water dimer as a concrete case. Keywords Quantum chemical topology • IQA • QTAIM • Energy partitioning • Water dimer • ANANKE • Pearson correlation Published as part of the special collection of articles "First European Symposium on Chemical Bonding".

Molecular Physics, 2015

Quantifying an atom's transferability, in a force field context, demands a quantitative understanding of how an atom 'experiences' the surrounding environment both intra-atomically and interatomically. Here we investigate the intra-atomic (E intra A ) viewpoint through the study of the atoms C α , H α , N, O, and S in a series of 'mono'-, tri-and penta-peptides. The remaining inter-atomic viewpoint consists of an electrostatic (via multipole moments), exchange and correlation components respectively, of which the electrostatic component has been previously reported. Together these four energy components, as calculated from the Interacting Quantum Atoms (IQA) partitioning approach, express the foundation of the Quantum Chemical Topological Force Field (QCTFF). In order to have transferability within a force field, smaller sample systems must be calculated and developed as representative of larger target systems. The C α , H α , N, O and S atoms in a tri-peptide are energetically comparable to those in their pentapeptide configurations, within 2.1 kJ/mol in absolute value (1 exception). Across all five elements, this energy difference is on average ∼0.3 kJ/mol. On average, the tri-peptide sample systems represent a ∼8.2 Å atomic horizon around the central atoms of interest. Thus, both the previous knowledge of the ∼10.3 Å horizon sphere and ∼0.4 kJ/mol error required by the electrostatic multipole moments, determine how two of the four key QCTFF energy components are affected by an atom's molecular environment. Dedication: It is a pleasure to contribute to a special issue in honour of Andreas Savin, a most generous host with whom I have enjoyed several discussions. As a deep and valiant thinker, a true scientist such as Andreas will surely continue to work in this capacity beyond his official retirement.

Analyst, 2015

By looking back on the history of Raman Optical Activity (ROA), the present article shows that the success of this analytical technique was for a long time hindered, paradoxically, by the deep level of detail and wealth of structural information it can provide. Basic principles of the underlying theory are discussed, to illustrate the technique's sensitivity due to its physical origins in the delicate response of molecular vibrations to electromagnetic properties. Following a short review of significant advances in the application of ROA by UK researchers, we dedicate two extensive sections to the technical and theoretical difficulties that were overcome to eventually provide predictive power to computational simulations in terms of ROA spectral calculation. In the last sections, we focus on a new modelling strategy that has been successful in coping with the dramatic impact of solvent effects on ROA analyses. This work emphasises the role of complementarity between experiment and theory for analysing the conformations and dynamics of biomolecules, so providing new perspectives for methodological improvements and molecular modelling development. For the latter, an example of a next-generation force-field for more accurate simulations and analysis of molecular behaviour is presented. By improving the accuracy of computational modelling, the analytical capabilities of ROA spectroscopy will be further developed so generating new insights into the complex behaviour of molecules. Shaun T. Mutter obtained his PhD in computational chemistry from Cardiff University in 2013 and is currently a postdoctoral research associate in the Manchester Institute of Biotechnology at the University of Manchester. His research interests lie in the calculation and analysis of Raman optical activity spectra of biomolecules, with a particular emphasis on carbohydrates. François Zielinski Francois Zielinski In Rouen (France), François Zielinski graduated with a MSc in Chemical Engineering (INSA, 2008), a PhD in Theoretical Chemistry (Univ., 2012). He joined thereafter the group of Pr. Popelier as a postdoctoral research associate at the University of Manchester. Besides Quantum Chemical Topology, he pursues an interest in computational and modelling techniques.

RSC Advances, 2015

The nature of the Ru–NO interaction before and after reduction of cis-[Ru(NO)(NO2)L1–4]q complexes is modulated by the coordination environment of the metallic center, resulting in more labile on complexes with weak π-acceptor ligands.

Theoretical Chemistry Accounts, 2018

Biphenyl is a prototype molecule, the study of which is important for a proper understanding of stereo-electronic effects. In the gas phase it has an equilibrium central torsion angle of ~ 45° and shows both a planar (0°) and a perpendicular (90°) torsional energy barrier. The latter is analysed for the first time. We use the newly proposed REG method, which is an exhaustive procedure that automatically ranks atomic energy contributions according to their importance in explaining the energy profile of a total system. Here, the REG method operates on energy contributions computed by the interacting quantum atoms method. This method is minimal in architecture and provides a crisp picture of well-defined and well-separated electrostatic, steric and exchange (covalent) energies at atomistic level. It is shown that the bond critical point occurring between the orthohydrogens in the planar geometry has been wrongly interpreted as a sign of repulsive interaction. A convenient metaphor of analysing football matches is introduced to clarify the role of a REG analysis. Quantum chemical topology • QTAIM • IQA • Relative energy gradient (REG) • Biphenyl • Energy barrier Published as part of the special collection of articles In Memoriam of János Ángyán

Journal of Computational Chemistry, 2017

Accurate description of the intrinsic preferences of amino acids is important to consider when developing a biomolecular force field. In this study, we use a modern energy partitioning approach called Interacting Quantum Atoms to inspect the cause of the u and w torsional preferences of three dipeptides (Gly, Val, and Ile). Repeating energy trends at each of the molecular, functional group, and atomic levels are observed across both (1) the three amino acids and (2) the u/w scans in Ramachandran plots. At the molecular level, it is surprisingly electrostatic destabilization that causes the high-energy regions in the Ramachandran plot, not molecular steric hindrance (related to the intra-atomic energy). At the functional group and atomic levels, the importance of key peptide atoms ) and some sidechain hydrogen atoms (H c ) are identified as responsible for the destabilization seen in the energetically disfavored Ramachandran regions. Consistently, the O i-1 atoms are particularly important for the explanation of dipeptide intrinsic behavior, where electrostatic and steric destabilization unusually complement one another. The findings suggest that, at least for these dipeptides, it is the peptide group atoms that dominate the intrinsic behavior, more so than the sidechain atoms. V