Inorganics, 4, 36, 2016

DOI:10.3390/inorganics4040036

A. Molloy, G. Sánchez-Sanz, D. G. Gilheany

PP-Rotation, P-inversion and metathesis in diphosphines studied by DFT calculations: comments on some literature conflicts

The potential energy surface for internal rotation about the phosphorus-phosphorus bond was calculated at the PCMDCM/B3LYP/6-311++G(d,p) computational level for a set of eight symmetrical, unsymmetrical and P-stereogenic diphosphines; H4P2, Me4P2, (CF3)4P2, Ph4P2, Me2P-P(CF3)2, Me2P-PPh2, and the meso- and dl-isomers of Me(CF3)P-PMe(CF3) and MePhP-PMePh. Certain trends in the data were elucidated and compared with conflicting data from the literature regarding the relative population of anti and gauche rotational isomers. The pyramidal inversion barriers (stereomutation barriers in P-stereogenic cases) for the same set of diphosphines was estimated through the inversion transition states and also compared to literature values. Finally, the Me4P2 + (CF3)4P2 → 2 Me2(CF3)2Pmetathesis reaction was also explored to evaluate its feasibility versus inversion. The finding of larger barriers inthe metathesis than in the inversion rules in favour of an inversion mechanism for the stereomutation of P-stereogenic diphosphines.

New J. Chem, 40, 9060, 2016

DOI:10.1039/C6NJ01334A

D. Quiñonero, A. Bauzá, G. Sánchez-Sanz, C. Trujillo, I. Alkorta, J. Elguero

Weak interactions within nitryl halide heterodimers

A theoretical study of nitryl halide heterodimers has been carried out by means of SCS-RI-MP2 and CCSD(T) at the complete basis set (CBS) calculations. For this purpose, 66 heterodimers have been characterized as minima and arranged in six groups depending on the interactions involved and geometrical arrangements. The CCSD(T)/CBS interaction energies vary between –0.6 and –11.1 kJ mol–1. The heavier the halogen atoms the larger the interaction energies are. Natural bond orbital (NBO) and “atoms-in-molecules” (AIM) theories were used to analyze the complexes, confirming the presence of halogen, chalcogen, and π-hole interaction bonds. The largest charge-transfer energy contributions are found for halogen bonded complexes (up to 29.1 kJ mol–1). Moreover the physical nature of the interactions has been studied by means of SAPT calculations, concluding that dispersion is the major source of attraction, although electrostatics is important in halogen bonded complexes.

PLoS Comput. Bio. 12, e1005051, 2016

DOI:10.1371/journal.pcbi.1005051

G. Sánchez-Sanz, B. Tywoniuk, D. Matallanas, D. Romano, L. Nguyen, B. N. Khodolenko, E. Rosta, W. Kolch, N.-V. Buchete

SARAH Domain-mediated MST2-RASSF Dimeric Interactions

RASSF enzymes act as key apoptosis activators and tumour suppressors, being downregulated in many human cancers, although their exact regulatory roles remain unknown. A key downstream event in the RASSF pathway is the regulation of MST kinases, which are main effectors of RASSF-induced apoptosis. The regulation of MST1/2 includes both homo- and hetero-dimerization, mediated by helical SARAH domains, though the underlying molecular interaction mechanism is unclear. Here, we study the interactions between RASSF1A, RASSF5, and MST2 SARAH domains by using both atomistic molecular simulation techniques and experiments. We construct and study models of MST2 homodimers and MST2-RASSF SARAH heterodimers, and we identify the factors that control their high molecular stability. In addition, we also analyse both computationally and experimentally the interactions of MST2 SARAH domains with a series of synthetic peptides particularly designed to bind to it, and demonstrate that our approach can be used to design new anti-cancer drugs. 

Tetrahedron, 72, 4690, 2016

DOI:10.1016/j.tet.2016.06.050

G. Sánchez-Sanz, C. Trujillo, I. Alkorta, J. Elguero

Aromatic changes in isoelectronic derivatives of phenalenyl radicals by central carbon replacement

A computational study of the aromatic characteristics of phenalenyl (PLY) upon replacement of the central carbon atom by Si, Ge, N, P, As, B, Al and Ga atoms comprising isoelectronic series with different charges (0, +1, –1) has been performed at the B3LYP/6-311++G(d,p) level. Two different geometries have been obtained, one planar and another one bowl-shaped. PLY derivatives exhibit a loss of the aromatic character in all cases indicated by NICS (Nucleus-Independent Chemical Shifts) values. These aromatic features are also in agreement with the pyramidalisation undergone by the central atom. The current density maps for those planar systems corroborate NICS findings. These variations in the aromaticity have been rationalised in terms of charge localisation. Harmonic oscillator model of aromaticity (HOMA) and para-delocalisation indices (PDI) have been used to evaluate the electron density delocalisation. HOMA values do not correlate with NICS but PDI indices follow the same trend than NICS.

Comput. Theor. Chem. 1090, 171, 2016

DOI:10.1016/j.comptc.2016.06.020

G. Sánchez-Sanz, C. Trujillo, I. Alkorta

Structure, binding energy and chiral discrimination in oxathiirane homodimers.

Oxathiirane (XHCSO) homodimers bonded by hydrogen bonds (HB) and chalcogen bonds (YB) were studied at the Møller-Plesset (MP2) computational level. Binding energies obtained at the Coupled-Cluster level up to the Complete Basis Set limit [CCSD(T)/CBS] indicate that HB complexes present stronger binding modes than the YB ones.  In terms of chiral discrimination energy, R,S complexes are favored over R,R ones with the exceptions of SiCl3 and SiF3 derivatives. Natural Bond Orbital (NBO) results are in agreement with the interaction energies in the case of the HB complexes, but could not discriminate between R,R and R,S in the YB complexes. The lack of correlation between molecular electrostatic values on the 0.001 a.u. and binding energies, in addition to the discrepancies between Atoms in Molecules (AIM) and NBO results may suggest that the electrostatics is not the dominant term in the interaction energy. This was corroborated by the Localized Molecular Orbital Energy Decomposition Analysis (LMOEDA) calculations which showed that the exchange and dispersion terms are the most important attractive components for all the complexes studied, contributing up to 50.6 and 42.5% to the total attractive forces respectively.

Theor. Chem. Acc. 135,140, 2016

DOI:10.1007/s00214-016-1895-8

G. Sánchez-Sanz, C. Trujillo, I. Alkorta, J. Elguero

Competition between intramolecular hydrogen and pnictogen bonds in protonated systems

A theoretical study of the competition between hydrogen (HB) and pnictogen bonds (ZB) in three different families of compounds, (Z)-1,2-disubstituted ethenes (Eth), 1,2-disubstituted benzenes (Phe) and 1,8-disubstituted naphthalenes (Naph), with a charged group, ZH3+ and a neutral one, Z'H2 (Z, Z' = N, P, As) as interacting moieties, has been carried out. In those structures with a NH3+ motif, intramolecular hydrogen bond structures are minima while pnictogen interactions are transition states. The opposite is true for PH3+ and AsH3+ moieties. An analysis of isodesmic energies (Eiso), interaction energies (Eb) and deformation energies (Edef), shows than in Eth derivatives, the most stable compound corresponds to P+–N ZB while in the Phe and Naph ones, the N+–N HB interaction presents the largest negative isodesmic energy. Also, Eth and Phe derivatives show negative Eiso values for all the compounds under study, however in some cases of Naph derivatives positive isodesmic energies have been found. The Atoms in Molecules (AIM) analysis of the electron density, Natural Bond Orbital (NBO) second order orbital energies and electron density shift maps (EDS) have been used to better understand these intramolecular interactions.  

Biophys. J. 110 (Suppl. 1) , 379a, 2016

DOI:10.1016/j.bpj.2015.11.2046

A. Crowe, G. Sánchez-Sanz, B. Tywoniuk, Denis. C. Shields, N.-V. Buchete

Coarse Master Equation-Based Analysis of N-Methylation and Temperature Effects on the Dynamics of Cyclic Peptides

Cyclosporin A (CsA) is a cyclic peptide widely used as an important immunosuppressant drug to prevent organ rejection following transplants. It is eleven residues in length, cyclized head-to-tail and is multiply N-methylated and largely hydrophobic, which makes it an excellent template for drug design. This study elucidates the important effects of N-methylation and temperature on the conformational dynamics, and specifically in altering the intramolecular hydrogen bond geometries of N-methylated cyclic peptides, such as CsA. We have run several normal and high-temperature molecular dynamics (MD) simulations of CsA and of a de-methylated variant (dCsA) whereby all backbone N-methyl groups have been removed. We have found that the numerous N-methyl sites introduce a large degree of conformational specificity to CsA by modulating the formation of intramolecular hydrogen bonds. Geometric measures such as cross-sectional distances, solvent accessible surface area (SASA), and intramolecular hydrogen bonding are used to explore and compare the conformational ensemble of CsA and dCsA. We use data-driven methods to cluster the conformational states, providing an increasingly automatic method of state identification. Representative structures are analyzed further using a coarse master equation-based kinetic analysis method. This formalism can be used for a systematic comparison of the conformational dynamics of cyclic peptides in MD simulations in explicit water, under various conditions, quantifying the mechanisms and effects of N-methylation and the T-dependence.

Phys. Chem. Chem. Phys. 18, 9148, 2016

DOI:10.1039/C6CP00227G

G. Sánchez-Sanz, C. Trujillo, I. Alkorta, J. Elguero 

Modulating Intramolecular P···N Interactions

A computational study of the intramolecular pnictogen bond in 8-phosphinonaphthalen-1-amine derivatives (1-NX2, 8-PX2 with X = H, F, Cl, Br, CH3, CN and NC), proton sponge analogues, has been carried out to determine their structural and geometric parameters, interaction energies and electronic properties such as electron density of the intramolecular interaction. Our results show that substitution of H atoms in the PH2 group by electron withdrawing groups on the Lewis acid moiety strengthen the P•••N pnictogen bond, evidenced by increasing the electron density values at the bond critical point and by shorter distances. However, substitutions on the Lewis base moiety (NX2) show weaker P•••N interactions than when the substitution is done on the Lewis acid counterpart (PX2). Nevertheless, in all cases, pnictogen bonds are enhanced upon substitution with respect to the parent 1-NH2, 8-PH2 system. Second-order orbital interaction energies, electron density maps, electron delocalization function and charge transfer corroborate the evolution of the P•••N strength upon substitution.

ChemPhysChem,17, 395, 2016

DOI:10.1002/cphc.201501019

C. Trujillo, G. Sánchez-Sanz

Study of the π-π Stacking Interactions and Aromaticity in Polycyclic Aromatic Hydrocarbons and DNA/RNA Bases Complexes 

We have analysed the interactions and aromaticity electron density delocalisation observed in π-π  complexes between phenalenyl radical and acenaphthylene, and the DNA and RNA nucleobases (adenine, guanine, cytosine, thymine and uracil). Interaction energies have been obtained a M06–2X /6–311++G(2df,p) in gas phase and PCM-Water conditions. In both cases, Phe and Ace, the complexes formed with guanine are the most stable one.  Atoms in molecules (AIM) and Natural Bond Orbital (NBO) results reveal weak  π-π interactions between both interacting moieties, characterised by bond critical points between C•••C and C•••N atoms. Nucleus Independent Chemical Shifts (NICS) indicate a retaining of the aromatic character of the monomers in the outer region of the complex. FLU indexes reveal a loss of the electron delocalisation upon complexation in all cases except guanine complexes. Nevertheless, the interface region reveals large negative NICS values which cannot be associated to increase of the aromaticity or electron density delocalisation, but to magnetic couplings of both molecules leading to unrealistic description of the aromatic behaviour in that region.

Brief. Bioinform., 17, 593, 2016

DOI:10.1093/bib/bbv070

G. Sánchez-Sanz, D. Matallanas, L. K. Nguyen, B. N. Khodolenko, E. Rosta, W. Kolch, N.-V. Buchete

MST2-RASSF Protein-Protein Interactions Through SARAH Domains

The detailed, atomistic-level understanding of molecular signaling along the tumor-suppressive Hippo signaling pathway, which controls tissue homeostasis by balancing cell proliferation and death through apoptosis, is a promising avenue for the discovery of novel anticancer drug targets. The activation of kinases such as MST1 and MST2 – modulated through both homo- and hetero-dimerization (e.g., interactions with RASSF enzymes) – is a key upstream event in this pathway and remains poorly understood. On the other hand, RASSFs (such as RASSF1A or RASSF5) act as important apoptosis activators and tumor suppressors, although their exact regulatory roles are also unclear. We review recent molecular studies of signaling along the Ras-RASSF-MST pathway, which controls growth and apoptosis in eukaryotic cells, including a variety of modern molecular modeling and simulation techniques. Using recently available structural information, we discuss the complex regulatory scenario according to which RASSFs perform dual signaling functions, either preventing or promoting MST2 activation, and thus controlling cell apoptosis. Here, we focus on recent studies highlighting the special role being played by the specific interactions between the helical SARAH domains of MST2 and RASSF1a or RASSF5 enzymes. These studies are crucial for integrating atomistic-level mechanistic information about the structures and conformational dynamics of interacting proteins, with information available on their system-level functions in cellular signaling.

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