Showing papers by "Pavel Hobza published in 2018"

Non-covalent control of spin-state in metal-organic complex by positioning on N-doped graphene

Abstract: Nitrogen doping of graphene significantly affects its chemical properties, which is particularly important in molecular sensing and electrocatalysis applications. However, detailed insight into interaction between N-dopant and molecules at the atomic scale is currently lacking. Here we demonstrate control over the spin state of a single iron(II) phthalocyanine molecule by its positioning on N-doped graphene. The spin transition was driven by weak intermixing between orbitals with z-component of N-dopant (pz of N-dopant) and molecule (dxz, dyz, dz2) with subsequent reordering of the Fe d-orbitals. The transition was accompanied by an electron density redistribution within the molecule, sensed by atomic force microscopy with CO-functionalized tip. This demonstrates the unique capability of the high-resolution imaging technique to discriminate between different spin states of single molecules. Moreover, we present a method for triggering spin state transitions and tuning the electronic properties of molecules through weak non-covalent interaction with suitably functionalized graphene.

Comparison of the DFT-SAPT and Canonical EDA Schemes for the Energy Decomposition of Various Types of Noncovalent Interactions

Abstract: Interaction energies computed with density functional theory can be divided into physically meaningful components by symmetry-adapted perturbation theory (DFT-SAPT) or the canonical energy decomposition analysis (EDA). In this work, the decomposition results obtained by these schemes were compared for more than 200 hydrogen-, halogen-, and pnicogen-bonded, dispersion-bound, and mixed complexes to investigate their similarity in the evaluation of the nature of noncovalent interactions. BLYP functional with D3(BJ) correction was used for the EDA scheme, whereas asymptotically corrected PBE0 functional for DFT-SAPT provided some of the best combinations for description of noncovalent interactions. Both schemes provide similar results concerning total interaction energies and insight into the individual energy components. For most complexes, the dominant energetic term was identified equally by both decomposition schemes. Because the canonical EDA is computationally less demanding than the DFT-SAPT, the forme...

Ranking Power of the SQM/COSMO Scoring Function on Carbonic Anhydrase II-Inhibitor Complexes.

Abstract: Accurate prediction of protein-ligand binding affinities is essential for hit-to-lead optimization and virtual screening. The reliability of scoring functions can be improved by including quantum effects. Here, we demonstrate the ranking power of the semiempirical quantum mechanics (SQM)/implicit solvent (COSMO) scoring function by using a challenging set of 10 inhibitors binding to carbonic anhydrase II through Zn2+ in the active site. This new dataset consists of the high-resolution (1.1-1.4 A) crystal structures and experimentally determined inhibitory constant (Ki ) values. It allows for evaluation of the common approximations, such as representing the solvent implicitly or by using a single target conformation combined with a set of ligand docking poses. SQM/COSMO attained a good correlation of R2 of 0.56-0.77 with the experimental inhibitory activities, benefiting from careful handling of both noncovalent interactions (e.g. charge transfer) and solvation. This proof-of-concept study of SQM/COSMO ranking for metalloprotein-ligand systems demonstrates its potential for hit-to-lead applications.

An Isolated Molecule of Iron(II) Phthalocyanin Exhibits Quintet Ground‐State: A Nexus between Theory and Experiment

Abstract: Iron(II) phthalocyanine (FePc) is an important member of the phthalocyanines family with potential applications in the fields of electrocatalysis, magnetic switching, electrochemical sensing, and phototheranostics. Despite the importance of electronic properties of FePc in these applications, a reliable determination of its ground-state is still challenging. Here we present combined state of the art computational methods and experimental approaches, that is, Mossbauer spectroscopy and Superconducting Quantum Interference Device (SQUID) magnetic measurements to identify the ground state of FePc. While the nature of the ground state obtained with density functional theory (DFT) depends on the functional, giving mostly the triplet state, multi-reference complete active space second-order perturbation theory (CASPT2) and density matrix renormalization group (DMRG) methods assign quintet as the FePc ground-state in gas-phase. This has been confirmed by the hyperfine parameters obtained from 57 Fe Mossbauer spectroscopy performed in frozen monochlorobenzene. The use of monochlorobenzene guarantees an isolated nature of the FePc as indicated by a zero Weiss temperature. The results open doors for exploring the ground state of other metal porphyrin molecules and their controlled spin transitions via external stimuli.

Imidazo[1,2-c]pyrimidin-5(6H)-one as a novel core of cyclin-dependent kinase 2 inhibitors: Synthesis, activity measurement, docking, and quantum mechanical scoring

Abstract: We report on the synthesis, activity testing, docking, and quantum mechanical scoring of novel imidazo[1,2-c]pyrimidin-5(6H)-one scaffold for cyclin-dependent kinase 2 (CDK2) inhibition. A series of 26 compounds substituted with aromatic moieties at position 8 has been tested in in vitro enzyme assays and shown to inhibit CDK2. 2D structure-activity relationships have ascertained that small substituents at position 8 (up to the size of naphtyl or methoxyphenyl) generally lead to single-digit micromolar IC50 values, whereas bigger substituents (substituted biphenyls) decreased the compounds' activities. The binding modes of the compounds obtained using Glide docking have exhibited up to 2 hinge-region hydrogen bonds to CDK2 and differed in the orientation of the inhibitor core and the placement of the 8-substituents. Semiempirical quantum mechanics-based scoring identified probable favourable binding modes, which will serve for future structure-based design and synthetic optimization of substituents of the heterocyclic core. In summary, we have identified a novel core for CDK2 inhibition and will explore it further to increase the potencies of the compounds and also monitor selectivities against other protein kinases.

The role of the σ-holes in stability of non-bonded chalcogenide⋯benzene interactions: the ground and excited states

Abstract: The stability of the T-shaped and stacked complexes of benzene with methanethial (CH2S) and methaneselone (CH2Se) and their difluoro-, dichloro-, dibromo-derivatives is investigated in their ground and first electronic excited states by means of the SCS-ADC2 method. The origin of the stabilization in the ground state is discussed based on the results of calculations performed using the DFT-SAPT method. Calculations show that the stability of the T-shaped conformers increases upon electronic excitation, while it decreases for most of the stacked conformers. Both effects are explained by the changes in the electrostatic potential (ESP) of isolated monomers upon the electronic excitation.

Sequential BN-doping induced tuning of electronic properties in zigzag-edged graphene nanoribbons: a computational approach

Abstract: We employed first-principles methods to elaborate doping induced electronic and magnetic perturbations in one-dimensional zigzag graphene nanoribbon (ZGNR) superlattices. Consequently, the incorporation of alternate boron and nitrogen (hole–electron) centers into the hexagonal network instituted substantial modulations to electronic and magnetic properties of ZGNR. Our theoretical analysis manifested some controlled changes to electronic and magnetic properties of the ZGNR by tuning the positions (array) of impurity centers in the carbon network. Subsequent DFT based calculations also suggested that the site-specific alternate electron–hole (B/N) doping could regulate the band-gaps of the superlattices within a broad range of energy. The consequence of variation in the width of ZGNR in the electronic environment of the system was also tested. The systematic analysis of various parameters such as the structural orientations, spin-arrangements, the density of states (DOS), band structures, and local density of states envisioned a basis for the band-gap engineering in ZGNR and attributed to its feasible applications in next generation electronic device fabrication.

A Nexus between Theory and Experiment: Non-empirical Quantum Mechanical Computational Methodology Applied to Cucurbit[n]uril•Guest Binding Interactions

Abstract: A training set of eleven X-ray structures determined for biomimetic complexes between cucurbit[n]uril (CB[7 or 8]) hosts and adamantane-/diamantane ammonium/aminium guests were studied with DFT-D3 quantum mechanical computational methods to afford ΔGcalcd binding energies. A novel feature of this work is that the fidelity of the BLYP-D3/def2-TZVPP choice of DFT functional was proven by comparison with more accurate methods. For the first time, the CB[n]⋅guest complex binding energy subcomponents [for example, ΔEdispersion, ΔEelectrostatic, ΔGsolvation, binding entropy (−TΔS), and induced fit Edeformation(host), Edeformation(guest)] were calculated. Only a few weeks of computation time per complex were required by using this protocol. The deformation (stiffness) and solvation properties (with emphasis on cavity desolvation) of cucurbit[n]uril (n=5, 6, 7, 8) isolated host molecules were also explored by means of the DFT-D3 method. A high ρ2=0.84 correlation coefficient between ΔGexptl and ΔGcalcd was achieved without any scaling of the calculated terms (at 298 K). This linear dependence was utilized for ΔGcalcd predictions of new complexes. The nature of binding, including the role of high energy water molecules, was also studied. The utility of introduction of tethered [-(CH2)nNH3]+ amino loops attached to N,N-dimethyl-adamantane-1-amine and N,N,N′,N′-tetramethyl diamantane-4,9-diamine skeletons (both from an experimental and a theoretical perspective) is presented here as a promising tool for the achievement of new ultra-high binding guests to CB[7] hosts. Predictions of not yet measured equilibrium constants are presented herein.

Understanding the non-covalent interaction mediated modulations on the electronic structure of quasi-zero-dimensional graphene nanoflakes

Abstract: In recent years, magnetic or electric field induced modulations on the electronic environment of single molecular systems are common practice. In this particular study, we have instigated the possibility of controlling the electronic and spin-dependent properties of hydrogen-terminated graphene fragments, so-called graphene nanoflakes (GNF), using weak non-covalent interactions as the external stimuli. The topological frustration in the graphene fragment appreciated the compelling electronic behavior of the system. This leads to some unorthodox spin-distribution in the system and it is possible to synchronize this electronic perturbation switching through a non-covalent interaction. These findings institute a new avenue for sculpting such donor-acceptor composites as self-regulated spintronic devices in next generation electronics.

Quantum Mechanical and Molecular Mechanical Calculations on Substituted Boron Clusters and Their Interactions with Proteins

Abstract: Medicinal chemistry entails not only synthesis but also compound design. The role of rational drug design has been boosted in recent decades through the use of computer‐ aided drug design, either ligand‐ or structure‐based [1]. The former area makes heavy use of statistics and chemi‐informatics to set up dependencies between the physicochemical properties of the compounds and their biological activities. Although some properties, such as the lipophilicity (expressed as the n‐octanol/water partition coefficient, logP), can also be evaluated computationally by quantum mechanical (QM) or molecular mechanical (MM) methods, ligand‐based drug design is not the focus of this chapter. On the contrary, we discuss here structure‐based drug design, which uses three‐ dimensional (3D) structures of protein–ligand complexes to estimate affinities. The geometries are most often determined experimentally by X‐ray crystallography or nuclear magnetic resonance (NMR). In computer‐aided structure‐based drug design, the ligand’s binding pose within the protein is predicted by docking, a task that has practically been mastered for the broad organic chemistry space [2]. Scoring is thereafter used to assess which of the poses represent the native complex and to rank the compounds by affinity. In contrast, this task has, until recently, been deemed unsolved [3]. We have approached the low reliability of scoring by developing a QM‐based scoring function [4]. Its fundamental principle is QM treatment of protein–ligand noncovalent interactions and solvation [5]. We showed that such an approach can be advantageously used to unequivocally identify the ligand native pose [6], reproduce binding affinity in a series of ligands to various protein targets [5], and describe nonclassical noncovalent interactions, such as halogen bonds [7] or even covalently binding inhibitors [8]. Based on this extensive experience of ours with organic ligands and a decade‐long experience with calculations of boron clusters bound to proteins [9], we affirm that QM scoring is a general solution to the affinity prediction of boron cluster/protein binding. Quantum Mechanical and Molecular Mechanical Calculations on Substituted Boron Clusters and Their Interactions with Proteins Jindřich Fanfrlík, Adam Pecina, Jan Řezáč, Pavel Hobza, and Martin Lepšík*

Various types of non-covalent interactions contributing towards crystal packing of halogenated diphospha-dicarbaborane with an open pentagonal belt

Abstract: We have prepared 3-Cl-10-I-nido-7,8,9,11-P2C2B7H7 by the reaction of 3-Cl-nido-7,8,9,11-P2C2B7H8 with I2 in the presence of AlCl3. The product was obtained in a yield of 49% and was characterized by NMR spectroscopy and X-ray crystallography. Quantum chemical calculations have demonstrated that the crystal structure is stabilized by hydrogen, dihydrogen and pnictogen bonds.