Temperature-Induced Restructuring of Mycolic Acid Bilayers Modeling the Mycobacterium tuberculosis Outer Membrane: A Molecular Dynamics Study.

The emergence of new drug-resistant strains of the tuberculosis pathogen Mycobacterium tuberculosis (Mtb) is a new challenge for modern medicine. Its resistance capacity is closely related to the properties of the outer membrane of the Mtb cell wall, which is a bilayer membrane formed by mycolic acids (MAs) and their derivatives. To date, the molecular mechanisms of the response of the Mtb outer membrane to external factors and, in particular, elevated temperatures have not been sufficiently studied. In this work, we consider the temperature-induced changes in the structure, ordering, and molecular mobility of bilayer MA membranes of various chemical and conformational compositions. Using all-atom long-term molecular dynamics simulations of various MA membranes, we report the kinetic parameters of temperature-dependent changes in the MA self-diffusion coefficients and conformational compositions, including the apparent activation energies of these processes, as well as the characteristic times of ordering changes and the features of phase transitions occurring over a wide range of elevated temperatures. Understanding these effects could be useful for the prevention of drug resistance and the development of membrane-targeting pharmaceuticals, as well as in the design of membrane-based materials.

Free Energy Barriers for Passive Drug Transport through the Mycobacterium tuberculosis Outer Membrane: A Molecular Dynamics Study.

The emergence of multi-drug-resistant tuberculosis strains poses a significant challenge to modern medicine. The development of new antituberculosis drugs is hindered by the low permeability of many active compounds through the extremely strong bacterial cell wall of mycobacteria. In order to estimate the ability of potential antimycobacterial agents to diffuse through the outer mycolate membrane, the free energy profiles, the corresponding activation barriers, and possible permeability modes of passive transport for a series of known antibiotics, modern antituberculosis drugs, and prospective active drug-like molecules were determined using molecular dynamics simulations with the all-atom force field and potential of mean-force calculations. The membranes of different chemical and conformational compositions, density, thickness, and ionization states were examined. The typical activation barriers for the low-mass molecules penetrating through the most realistic membrane model were 6-13 kcal/mol for isoniazid, pyrazinamide, and etambutol, and 19 and 25 kcal/mol for bedaquilin and rifampicin. The barriers for the ionized molecules are usually in the range of 37-63 kcal/mol. The linear regression models were derived from the obtained data, allowing one to estimate the permeability barriers from simple physicochemical parameters of the diffusing molecules, notably lipophilicity and molecular polarizability.

Conformational Dynamics and Stability of Bilayers Formed by Mycolic Acids from the Mycobacterium tuberculosis Outer Membrane.

Bilayers of mycolic acids (MAs) form the outer membrane of Mycobacterium tuberculosis that has high strength and extremely low permeability for external molecules (including antibiotics). For the first time, we were able to study them using the all-atom long-term molecular dynamic simulations (from 300 ns up to 1.2 µs) in order to investigate the conformational changes and most favorable structures of the mycobacterial membranes. The structure and properties of the membranes are crucially dependent on the initial packing of the α-mycolic acid (AMA) molecules, as well as on the presence of the secondary membrane components, keto- and methoxy mycolic acids (KMAs and MMAs). In the case of AMA-based membranes, the most labile conformation is W while other types of conformations (sU as well as sZ, eU, and eZ) are much more stable. In the multicomponent membranes, the presence of the KMA and MMA components (in the W conformation) additionally stabilizes both the W and eU conformations of AMA. The membrane in which AMA prevails in the eU conformation is much thicker and, at the same time, much denser. Such a packing of the MA molecules promotes the formation of a significantly stronger outer mycobacterial membrane that should be much more resistant to the threatening external factors.

Unexpected polarization properties of sub-nanosized magnesium clusters.

The isotropic electrostatic polarizability (IEP) of sub-nanosized magnesium clusters Mg2-Mg32 was studied in an extensive set comprising 1237 structurally unique isomers. These isomers were found in the course of the global search for the potential energy surface minima of the magnesium clusters at the BP86/6-31G(d) level. The calculation of the polarizability at the same DFT level reveals an unexpected property of the IEP: the linear correlation between the polarizability of the most favorable isomers (and only them) and the cluster nuclearity n. Moreover, for each n, the most stable cluster isomer demonstrates nearly minimal IEP value among all found isomers of a given nuclearity. Surprisingly, these observed features are independent of the cluster structures which are quite different. We hypothesize that the energetic favorability of a cluster structure is related to their low polarizability. Apparently, the atoms forming the cluster tend to arrange themselves in such a way as to provide the most compact distribution of the cluster electron density. A possible explanation of the observed trends, their significance for cluster structure prediction, and the practical applications are discussed.

Machine Learning Prediction of Mycobacterial Cell Wall Permeability of Drugs and Drug-like Compounds.

The cell wall of Mycobacterium tuberculosis and related organisms has a very complex and unusual organization that makes it much less permeable to nutrients and antibiotics, leading to the low activity of many potential antimycobacterial drugs against whole-cell mycobacteria compared to their isolated molecular biotargets. The ability to predict and optimize the cell wall permeability could greatly enhance the development of novel antitubercular agents. Using an extensive structure-permeability dataset for organic compounds derived from published experimental big data (5371 compounds including 2671 penetrating and 2700 non-penetrating compounds), we have created a predictive classification model based on fragmental descriptors and an artificial neural network of a novel architecture that provides better accuracy (cross-validated balanced accuracy 0.768, sensitivity 0.768, specificity 0.769, area under ROC curve 0.911) and applicability domain compared with the previously published results.

Synthesis, Molecular Docking, In Vitro and In Vivo Studies of Novel Dimorpholinoquinazoline-Based Potential Inhibitors of PI3K/Akt/mTOR Pathway.

A (series) range of potential dimorpholinoquinazoline-based inhibitors of the PI3K/Akt/mTOR cascade was synthesized. Several compounds exhibited cytotoxicity towards a panel of cancer cell lines in the low and sub-micromolar range. Compound 7c with the highest activity and moderate selectivity towards MCF7 cells which express the mutant type of PI3K was also tested for the ability to inhibit PI3K-(signaling pathway) downstream effectors and associated proteins. Compound 7c inhibited the phosphorylation of Akt, mTOR, and S6K at 125-250 nM. It also triggered PARP1 cleavage, ROS production, and cell death via several mechanisms. Inhibition of PI3Kα was observed at a concentration of 7b 50 µM and of 7c 500 µM and higher, that can indicate minority PI3Kα as a target among other kinases in the titled cascade for 7c. In vivo studies demonstrated an inhibition of tumor growth in the colorectal tumor model. According to the docking studies, the replacement of the triazine core in gedatolisib (8) by a quinazoline fragment, and incorporation of a (hetero)aromatic unit connected with the carbamide group via a flexible spacer, can result in more selective inhibition of the PI3Kα isoform.

How Many Isomers Do Metallic Clusters Have? Case of Magnesium Clusters of up to 55 Atoms.

About 9000 structures of magnesium clusters Mgn (n = 2-13) generated via different methods were optimized at the DFT levels in order to estimate the number of all possible stable structures that can exist for the given cluster size (∼820,000 PES points were explored in total). It was found that the number of possible cluster isomers N quickly grows with a number of atoms n; however, it is significantly lower than the number of possible nonisomorphic graph structures, which can be drawn for the given n. At the DFT potential energy surface, we found only 543 local minima corresponding to the isomers of Mg2-Mg13. The number of isomers obtained in the DFT optimizations grows with n approximately as n4, whereas the N values extrapolated to the infinite generation process grow as n8. The cluster geometries obtained from the global DFT optimization were then used to adjust two empirical potentials of Gupta type (GP) and modified Sutton-Chen type (SCG3) describing the interactions between the magnesium atoms. Using these potentials, the extensive sets of structures Mg2-Mg55 (up to 30,000 clusters for each n) were optimized to obtain the dependence of the cluster isomer count on n in the continuous range of n = 2-30 and for selected n up to n = 55. It was found that the SCG3 potential, which is closer to the DFT results, gives a number of possible isomers growing as approximately n8.9, whereas GP potential results in the n4.3 dependence.

Dissolution of chitosan nanocrystals in aqueous media of different acidity. Molecular dynamic study.

The process of dissolution of chitosan nanocrystals with molecular mass of polymer up to 12.8 kDa in aqueous media of various pH was studied by molecular dynamic simulations with the use of the improved force field GROMOS 56ACARBO_CHT specially developed for the chitosan polymers description. The effect of the media acidity and polymer molecular weight on the dissolution process kinetics has been studied and the regression expressions for kinetic parameters were established. The calculated solution viscosity, Mark-Houwink-Sakurada equation parameters, and pH values of the dissolution beginning are in good agreement with the available experimental data. The uniform/non-uniform distribution of protonated amino groups and hydrogen bonds along the polymeric chains is found to be of key importance parameter for the dissolution process which can be considered as a criterion of dissolution ability.

Dependence of Anterior Active Rhinomanometry Indices on Nasal Obstructive Disorders in Children with Atopic Bronchial Asthma Complicated by Nasal Symptoms.

BACKGROUND: Atopic bronchial asthma (BA) in children is associated with upper airways pathology (UAP). Among them, a combination of allergic rhinitis (AR) and nasal obstructive disorders (NOD), including hypertrophy of the pharyngeal tonsil (HPT) and anomalies of the intranasal structures (AINS), is abundant. In such patients, anterior active rhinomanometry (AARM) is an important method of examining nasal patency. However, NOD can influence the AARM parameters in children with BA and nasal symptoms, and this effect must be taken into account in clinical practice. Study goal was to elucidate the effect of NOD on rhinomanometric parameters in this group of patients. METHODS: Total of 66 children with BA and AR were examined with AARM, rhinovideoendoscopy, spirometry, and standard clinical tests allowing revealing the structure of comorbid pathologies. In order to avoid the influence of anthropometric parameters of children and their age on AARM parameters, a special index of reduced total nasal airflow was used. RESULTS: It has been established that NOD, especially HPT, have a significant negative impact on the indices of anterior active rhinomanometry during the periods of both AR remission and AR exacerbation. The effect of AINS is much weaker and was remarkable only in combination with HPT.

Synthesis and biological evaluation of novel non-racemic indole-containing allocolchicinoids.

Two novel indole-containing allocolchicinoids were prepared from naturally occurring colchicine exploiting the Curtius rearrangement and tandem Sonogashira coupling/Pd-catalyzed cyclization as the key transformations. Their cytotoxic properties, apoptosis-inducing activity, tubulin assembly inhibition and short-time cytotoxic effects were investigated. Compound 7 demonstrated the most pronounced anti-cancer activity: IC50 < 1 nM, cell cycle arrest in the G2/M phase, 25% apoptosis induction, as well as lower destructive short-time effects on HT-29 cell line in comparison with colchicine. Docking studies for prepared indole-derived allocolchicine analogues were carried out.

Body Height of Children with Bronchial Asthma of Various Severities.

Influence of bronchial asthma (BA) severity on physical development in children patients was evaluated in comparison with healthy population. Materials and Methods. 1042 children and adolescents (768 boys) with atopic BA were evaluated. All children underwent standard examination in a clinical setting, including anthropometry. The control group included 875 healthy children of a comparable age (423 boys). Results. The fraction of patients with the normal, lower, and increased height among the whole group of patients with BA is close to the corresponding values in the healthy population (χ2 = 3.32, p = 0.65). The fraction of BA patients with the reduced physical development is increased monotonically and significantly when the BA severity increases: healthy group, 8.2% (72/875), BA intermittent, 4.2% (6/144), BA mild persistent 9% (47/520), BA moderate persistent, 11.7% (36/308), and BA severe persistent, 24.3% (17/70) (χ2 = 45.6, p = 0,0009). Conclusion. The fraction of the children with the reduced height is increased monotonically and significantly in the groups of increasing BA severities. At the same time, the fraction of such children in groups of intermittent and mild persistent BA practically does not differ from the conditionally healthy peers.

Modification of 56ACARBO force field for molecular dynamic calculations of chitosan and its derivatives.

The GROMOS 56ACARBO force field for the description of carbohydrates was modified for calculations of chitosan (poly-1,4-(N-acetyl)-ß-D-glucopyranosamine-2) with protonated and non-protonated amino groups and its derivatives. Additional parameterization was developed on the basis of quantum chemical calculations. The modified force field (56ACARBO_CHT) allows performing the molecular dynamic calculations of chitosans with different degrees of protonation corresponding to various acidity of medium. Test calculations of the conformational transitions in the chitosan rings and polymeric chains as well as the chitosan nanocrystal dissolution demonstrate good agreement with experimental data. Graphical abstract The GROMOS 56ACARBO_CHT force field allows performing the molecular dynamic calculations of chitosans with different types of amio-group: free, protonated, substituted.

Multiple coupling of silanes with imido complexes of Mo.

The bis(imido) complexes ((t)BuN[double bond, length as m-dash])2Mo(PMe3)(L) (L = PMe3, C2H4) react with up to three equivalents of silane PhSiH3 to give the imido-bridged disilyl silyl Mo(vi) complex ((t)BuN){µ-(t)BuN(SiHPh)2}Mo(H)(SiH2Ph)(PMe3)2 (3) studied by NMR, IR and X-ray diffraction. NMR data supported by DFT calculations show that complex 3 is an unusual example of a silyl hydride of Mo(VI), without significant SiH interaction. Mechanistic NMR studies revealed that silane addition proceeds in a stepwise manner via a series of Si-H∙∙∙M agostic and silanimine complexes whose structures were further elucidated by DFT calculations.

Unusual structure, fluxionality, and reaction mechanism of carbonyl hydrosilylation by silyl hydride complex [(ArN=)Mo(H)(SiH2Ph)(PMe3)3].

The reactions of bis(borohydride) complexes [(RN=)Mo(BH4)2(PMe3)2] (4: R = 2,6-Me2C6H3; 5: R = 2,6-iPr2C6H3) with hydrosilanes afford new silyl hydride derivatives [(RN=)Mo(H)(SiR'3)(PMe3)3] (3: R = Ar, R'3 = H2Ph; 8: R = Ar', R'3 = H2Ph; 9: R = Ar, R'3 = (OEt)3; 10: R = Ar, R'3 = HMePh). These compounds can also be conveniently prepared by reacting [(RN=)Mo(H)(Cl)(PMe3)3] with one equivalent of LiBH4 in the presence of a silane. Complex 3 undergoes intramolecular and intermolecular phosphine exchange, as well as exchange between the silyl ligand and the free silane. Kinetic and DFT studies show that the intermolecular phosphine exchange occurs through the predissociation of a PMe3 group, which, surprisingly, is facilitated by the silane. The intramolecular exchange proceeds through a new non-Bailar-twist pathway. The silyl/silane exchange proceeds through an unusual Mo(VI) intermediate, [(ArN=)Mo(H)2(SiH2Ph)2(PMe3)2] (19). Complex 3 was found to be the catalyst of a variety of hydrosilylation reactions of carbonyl compounds (aldehydes and ketones) and nitriles, as well as of silane alcoholysis. Stoichiometric mechanistic studies of the hydrosilylation of acetone, supported by DFT calculations, suggest the operation of an unexpected mechanism, in that the silyl ligand of compound 3 plays an unusual role as a spectator ligand. The addition of acetone to compound 3 leads to the formation of [trans-(ArN)Mo(OiPr)(SiH2Ph)(PMe3)2] (18). This latter species does not undergo the elimination of a Si-O group (which corresponds to the conventional Ojima's mechanism of hydrosilylation). Rather, complex 18 undergoes unusual reversible ß-CH activation of the isopropoxy ligand. In the hydrosilylation of benzaldehyde, the reaction proceeds through the formation of a new intermediate bis(benzaldehyde) adduct, [(ArN=)Mo(η(2)-PhC(O)H)2(PMe3)], which reacts further with hydrosilane through a η(1)-silane complex, as studied by DFT calculations.

Structure, Energy, and Vibrational Frequencies of Oxygen Allotropes On (n ≤ 6) in the Covalently Bound and van der Waals Forms: Ab Initio Study at the CCSD(T) Level.

Recent experiments on the UV and electron beam irradiation of solid O2 reveals a series of IR features near the valence antisymmetric vibration band of O3 which are frequently interpreted as the formation of unusual On allotropes in the forms of weak complexes or covalently bound molecules. In order to elucidate the question of the nature of the irradiation products, the structure, relative energies, and vibrational frequencies of various forms of On (n = 1-6) in the singlet, triplet, and, in some cases, quintet states were studied using the CCSD(T) method up to the CCSD(T,full)/cc-pCVTZ and CCSD(T,FC)/aug-cc-pVTZ levels. The results of calculations demonstrate the existence of stable highly symmetric structures O4 (D3h), O4 (D2d), and O6 (D3d) as well as the intermolecular complexes O2·O2, O2·O3, and O3·O3 in different conformations. The calculations show that the local minimum corresponding to the O3···O complex is quite shallow and cannot explain the ν3 band features close to 1040 cm(-1), as was proposed previously. For the ozone dimer, a new conformer was found which is more stable than the structure known to date. The effect of the ozone dimer on the registered IR spectra is discussed.

Quantum chemical study of the initial step of ozone addition to the double bond of ethylene.

The mechanisms of the initial step in chemical reaction between ozone and ethylene were studied by multireference perturbation theory methods (MRMP2, CASPT2, NEVPT2, and CIPT2) and density functional theory (OPW91, OPBE, and OTPSS functionals). Two possible reaction channels were considered: concerted addition through the symmetric transition state (Criegee mechanism) and stepwise addition by the biradical mechanism (DeMore mechanism). Predicted structures of intermediates and transition states, the energies of elementary steps, and activation barriers were reported. For the rate-determining steps of both mechanisms, the full geometry optimization of stationary points was performed at the CASPT2/cc-pVDZ theory level, and the potential energy surface profiles were constructed at the MRMP2/cc-pVTZ, NEVPT2/cc-pVDZ, and CIPT2/cc-pVDZ theory levels. The rate constants and their ratio for reaction channels calculated for both mechanisms demonstrate that the Criegee mechanism is predominant for this reaction. These results are also in agreement with the experimental data and previous computational results. The structure of DeMore prereactive complex is reported here for the first time at the CCSD(T)/cc-pVTZ and CASPT2/cc-pVDZ levels. Relative stability of the complexes and activation energies were refined by single-point energy calculations at the CCSD(T)-F12/VTZ-F12 level. The IR shifts of ozone bands due to formation of complexes are presented and discussed.

An unexpected mechanism of hydrosilylation by a silyl hydride complex of molybdenum.

Carbonyl hydrosilylation catalyzed by (ArN)Mo(H)(SiH(2)Ph)(PMe(3))(3) (3) is unusual in that it does not involve the expected Si-O elimination from intermediate (ArN)Mo(SiH(2)Ph)(O(i)Pr)(PMe(3))(2) (7). Instead, 7 reversibly transfers ß-CH hydrogen from the alkoxide ligand to metal.

Mechanism of Nitric Oxide Oxidation Reaction (2NO + O2 → 2NO2) Revisited.

The reaction between molecular oxygen and two nitric oxide(II) molecules is studied with high-level ab initio wave function methods, including geometry optimizations with coupled cluster (CCSD(T,full)/cc-pCVTZ) and complete active space with second order perturbation theory levels (CASPT2/cc-pVDZ). The energy at the critical points was refined by calculations at the CCSD(T,full)/aug-cc-pCVTZ level. The controversies found in the previous theoretical studies are critically discussed and resolved. The best estimate of the activation energy is 6.47 kJ/mol.

Quantum chemical study of trimolecular reaction mechanism between nitric oxide and oxygen in the gas phase.

Singlet and triplet potential energy surfaces of the reaction between molecular oxygen and two nitric oxide(II) molecules were studied by quantum chemical methods (coupled cluster, CASSCF, and density functional theory: B3LYP, TPSS, VSXC, BP86, PBE, B2-PLYP, B2K-PLYP). Elementary steps involving various N2O4 isomers (cyclic, cis-cis-, cis-trans-, trans-trans-ONOONO, cis- and trans-ONONO2, O2NNO2) were considered, as well as weakly bound molecular clusters preceding formation of O2NNO2, and Coupe-type quasi-aromatic hexagonal ring intermediate NO2.O2N. We found that activation energy strongly depends on the conformation of ONOONO peroxide, which is formed barrierlessly. The best agreements with experimental values were achieved by the B3LYP functional with aug-pc3 basis set. The lowest transition state (TS) energies correspond to the following reaction channel: 2NO + O2 (0 kJ/mol) --> cis-cis-ONOONO (-45 kJ/mol) --> TS1 --> NO2.O2N (-90 kJ/mol) --> TS2 --> cis-ONONO2 (-133 kJ/mol)--> TS3 --> trans-ONONO2 (-144 kJ/mol) --> TS4 --> O2NNO2 (-193 kJ/mol). A valley ridge inflection (VRI) point is located on the minimum energy path (MEP) connecting NO2.O2N and cis-ONONO2. The energy landscape between NO2.O2N and CC-TS2 can be classified as a downhill valley-pitchfork VRI bifurcation according to a recent classification of bifurcation events [Quapp, W. J. Mol. Struct. 2004, 95, 695-696]. The first and second transition states correspond to barrier heights of 10.6 and 37.0 kJ/mol, respectively. These values lead to the negative temperature dependence of the rate constant. The apparent activation enthalpy of the overall reaction was calculated to be Delta(r)H(0) = -4.5 kJ/mol, in perfect agreement with the experimental value.

Beta-agostic silylamido and silyl-hydrido compounds of molybdenum and tungsten.

Reactions of bis(imido) compounds (RN)(2)Mo(PMe(3))(n) (n = 2, R = (t)Bu; n = 3, R =2,6-dimethylphenyl (Ar') and 2,6-diisopropylphenyl (Ar)) and (RN)(2)W(PMe(3))(3) (R = 2,6-dimethylphenyl and 2,6-diisopropylphenyl) with silanes afford four types of products: the beta-agostic silylamido compounds (RN)(eta(3)-RN-SiR'(2)-H...)MCl(PMe(3))(2) (M = Mo and W), mono(imides) (RN)MCl(2)(PMe(3))(3) (M = Mo and W), silyl hydride bis(imido) derivative (ArN)(2)W(PMe(3))(H)(SiMeCl(2)), and Si-Cl...W bridged product (ArN)(eta(2)-ArN-SiHMeCl-Cl...)WCl(PMe(3))(2). Reactions of molybdenum compounds (RN)(2)Mo(PMe(3))(m) (m = 2 or 3) with mono- and dichlorosilanes HSiCl(n)R'(3-n) (R' = Me, Ph; n = 1,2) afford mainly the agostic compounds (RN)(eta(3)-RN-SiR'(2)-H...)MoCl(PMe(3))(2), accompanied by small amounts of mono(imido) derivatives (RN)MoCl(2)(PMe(3))(3). In contrast, the latter compounds are the only transition metal products in reactions with HSiCl(3), the silicon co-product being the silanimine dimer (RNSiHCl)(2). The reaction of (ArN)(2)W(PMe(3))(3) with HSiCl(2)Me under continuous removal of PMe(3) affords the silyl hydride species (ArN)(2)W(PMe(3))(SiMeCl(2))H, characterized by NMR and X-ray diffraction. This product is stable in the absence of phosphine, but addition of catalytic amounts of PMe(3) causes a fast rearrangement into the Si-Cl...W bridged product (ArN)(eta(2)-ArN-SiHMeCl-Cl...)WCl(PMe(3))(2). The mechanism of silane addition to complexes (RN)(2)Mo(PMe(3))(n) has been elucidated by means of density functional theory calculations of model complexes (MeN)(2)Mo(PMe(3))(n) (n = 1-3). Complex (MeN)(2)Mo(PMe(3))(2) is found to be the most stable form. It undergoes facile silane-to-imido addition reactions that afford silylamido hydride complexes stabilized by additional Si...H interactions. The ease of this addition increases from HSiMe(2)Cl to HSiCl(3), consistent with experimental observations. The most stable final products of silane addition are the agostic complexes (MeN)(eta(3)-MeN-SiR(2)-H...)MoCl(PMe(3))(2) (R(2) = Me(2), MeCl, Cl(2)) and Cl-bridged silylamido complexes (MeN)(eta(2)-MeN-SiRH-Cl...)MoCl(PMe(3))(2) (R = Me or Cl). In the case of HSiMeCl(2) addition the former is the most stable, but for HSiCl(3) addition the latter is the preferred product. In all cases, the isomeric silyl hydride species (MeN)(2)Mo(PMe(3))(H)(SiClR(2)) are less stable by about 6 kcal mol(-1). Silane additions to the imido ligand of the tris(phosphine) (MeN)(2)Mo(PMe(3))(3) afford octahedral silylamido hydride derivatives. The different isomers of these addition products are destabilized relative to (MeN)(2)Mo(PMe(3))(3) only by 7-24 kcal mol(-1) (for the HSiMe(2)Cl additions), but since the starting tris(phosphine) is 14.8 kcal mol(-1) less stable than (MeN)(2)Mo(PMe(3))(2), silane addition to the latter is a more preferred pathway. A double phosphine dissociation pathway via the species (MeN)(2)Mo(PMe(3)) was ruled out because this complex is by 24.7 kcal mol(-1) less stable than (MeN)(2)Mo(PMe(3))(2).