Distinct Energy Minima Research Articles

Phosphorylation, Mg-ADP, and Inhibitors Differentially Shape the Conformational Dynamics of the A-Loop of Aurora-A.

The conformational state of the activation loop (A-loop) is pivotal for the activity of most protein kinases. Hence, the characterization of the conformational dynamics of the A-loop is important to increase our understanding of the molecular processes related to diseases and to support the discovery of small molecule kinase inhibitors. Here, we carry out a combination of molecular dynamics (MD) and essential dynamics (ED) analyses to fully map the effects of phosphorylation, ADP, and conformation disrupting (CD) inhibitors (i.e., CD532 and MLN8054) on the dynamics of the A-loop of Aurora-A. MD revealed that the stability of the A-loop in an open conformation is enhanced by single phospho-Thr-288, while paradoxically, the presence of a second phosphorylation at Thr-287 decreases such stability and renders the A-loop more fluctuant in time and space. Moreover, we found that this post-translational modification has a significant effect on the direction of the A-loop motions. ED analysis suggests that the presence of the phosphate moiety induces the dynamics of Aurora-A to sample two distinct energy minima, instead of a single large minimum, as in unphosphorylated Aurora-A states. This observation indicates that the conformational distributions of Aurora-A with both single and double phospho-threonine modifications are remarkably different from the unphosphorylated state. In the closed states, binding of CD532 and MLN8054 inhibitors has the effect of increasing the distance of the N- and C-lobes of the kinase domain of Aurora-A, and the angle analysis between those two lobes during MD simulations showed that the N- and C-lobes are kept more open in presence of CD532, compared to MLN8054. As the A-loop is a common feature of Aurora protein kinases, our studies provide a general description of the conformational dynamics of this structure upon phosphorylation and different ligands binding.

Phase boundary anisotropy and its effects on the maze-to-lamellar transition in a directionally solidified Al[sbnd]Al2Cu eutectic

Solid-solid phase boundary anisotropy is a key factor controlling the selection and evolution of non-faceted eutectic patterns during directional solidification. This is most remarkably observed during the so-called maze-to-lamellar transition. By using serial sectioning, we followed the spatio-temporal evolution of a maze pattern over long times in a large AlAl2Cu eutectic grain with known crystal orientation of the Al and Al2Cu phases, hence known crystal orientation relationship (OR). The corresponding phase boundary energy anisotropy (γ-plot) was also known, as being previously estimated from molecular-dynamics computations. The experimental observations reveal the time-scale of the maze-to-lamellar transition and shed light on the processes involved in the gradual alignment of the phase boundaries to one distinct energy minimum which nearly corresponds to one distinct plane from the family {120}Al||{110}Al2Cu. This particular plane is selected due to a crystallographic bias induced by a small disorientation of the crystals relative to the perfect OR. The symmetry of the OR is thus slightly broken, which promotes lamellar alignment. Finally, the maze-to-lamellar transition leaves behind a network of fault lines inherited from the phase boundary alignment process. In the maze pattern, the fault lines align along the corners of the Wulff shape, thus allowing us to propose a link between the pattern defects and missing orientations in the Wulff shape.

Theoretical investigation of existence of meta-stability in iron and cobalt clusters

Nowadays considerable attention has been given for researches on magnetic properties of transition metal clusters (specifically FeN and CoN). This is because these clusters offer big hopes for the possibility of presenting significant magnetic anisotropy energy which is critical for technological applications. This study intends to find out the causes for the existence of the two states (ground and meta-stable) in Iron and Cobalt clusters. The study also explains the role of valence electrons for the existence of magnetism in the two states by using the concept of ionization potential, electron dipole polarizabilities, chemical hardness and softness of the clusters. Assuming that, when all itinerant electrons are at s-level and also at the d-level (ns=nandns→0.) the ground state and meta-stable state energies with distinct energy minima are (Egs=l/2n+εcn−2μBhnandEms=εdn−gμBhn) respectively. The findings also showed that polarizability of small cluster of the specified elements are increased compared with the bulk value, which means that there is an effective increase in the cluster radius due to the spilling out of the electronic charge. Furthermore, it is obvious that 4s electrons are more delocalized than the 3d electrons so that they spill out more than the 3d electrons. This leads to the conclusion that 4s electrons are primarily responsible for the enhanced polarizabilities and for shell structure effects. This indicates that polarizability at the meta-stable state is less than that of the ground state i.e. the meta-stable state loses its s electron. Therefore the two minima represent a ground state of configuration 3d↑53d↓2+δ4s2−δ with energy Egs and meta-stable state of configuration 3d↑53d↓3+δ4s1−δ with energy Ems for Co clusters and a ground state configuration 3d↑53d↓1+δ4s2−δ with energy Egs an meta-stable state of configuration 3d↑53d↓2+δ4s1−δ with energy Ems for Fe clusters. Hence, the existence of the two states (meta-stable & ground state) is due to the large disproportion in electronic configurations of the two clusters at their respective states. Furthermore, the chemical hardness and softness of the clusters also provide evidence for the existence of stability of the two states depending on the cluster size.

Dynamical properties and temperature induced molecular disordering ofLiBH4andLiBD4

We report on neutron powder-diffraction experiments, inelastic incoherent neutron-scattering experiments, and density-functional calculations on dynamics, order and disorder properties of ${\text{LiBH}}_{4}$ and ${\text{LiBD}}_{4}$. From refinement of ${\text{LiBD}}_{4}$ structure at 10 and 302 K, we found an almost ideal tetrahedral geometry of ${\text{BD}}_{4}$ ions (difference between shortest and longest interatomic distances is less than 4% for B-D bond, and less than 3% for D-D bond), close to the calculated geometry. A quantitative agreement was found between experimental and calculated anisotropic temperature factors of individual atoms. For phonon energies $<15\text{ }\text{meV}$, the phonon density of states of ${\text{LiBH}}_{4}$ in the low-temperature phase depends quadratically on the phonon energy while for the high-temperature phase a linear dependence is observed, revealing a high lattice anharmonicity in the high-temperature phase. Moreover, an increased phonon density of states at low energies in the high-temperature phase compared to the low-temperature phase give a direct evidence for disorder in the high-temperature phase of ${\text{LiBH}}_{4}$ of the hydrogen sublattice which can originate from orientational disorder of ${\text{BH}}_{4}$ units. Potential energy landscape for rotation of ${\text{BH}}_{4}$ indicates that fairly localized minima and barriers higher than 0.6 eV exist in the low-temperature phase, i.e., ordered ${\text{BH}}_{4}$ ions. The high-temperature structure shows shallow barriers of $\ensuremath{\sim}0.2\text{ }\text{eV}$ without distinct energy minima, i.e., orientation of a single ${\text{BH}}_{4}$ unit cannot be precisely defined. This corroborates the large thermal displacements observed in diffraction studies and high disorder of ${\text{BH}}_{4}$ ions deduced from experimental partial phonon density of states in the high-temperature phase.

A Novel Facet of Carbonyliron-Diene Photochemistry: The η4-s-transIsomer of the Classical Fe(CO)3(η4-s-cis-1,3-butadiene) Discovered by Time-Resolved IR Spectroscopy and Theoretically Examined by Density Functional Methods

The photolysis of Fe(CO)3(η4-s-cis-1,3-butadiene) (1) and Fe(CO)4(η2-1,3-butadiene) (2), formerly studied in low-temperature matrixes, is reexamined in cyclohexane solution at ambient temperature using time-resolved IR spectroscopy in the ν(CO) region. Flash photolysis of 2 (λexc = 308 nm) generates Fe(CO)3(η4-s-trans-1,3-butadiene) (5) as a transient product, which then rearranges to form the classical η4-s-cis-1,3-butadiene complex 1. Species 5, previously addressed as the coordinately unsaturated Fe(CO)3(η2-1,3-butadiene) (3), is also photogenerated from 1, in this case along with the very short-lived CO loss fragment Fe(CO)2(η4-1,3-butadiene) (τ < 4 μs under CO atmosphere). It decays by temperature-dependent first-order kinetics (τ = 13 ms at 25 °C; ΔH⧧ = 17.3 kcal·mol-1) with nearly complete recovery of 1. According to density functional calculations at the BP86 level of theory, 5 resides in a distinct energy minimum, 20.3 kcal·mol-1 above 1 and separated from it by a barrier of 15.0 kcal·mol-1. Its ...

A Density Functional Study of Interactions at the Metal–Ceramic Interfaces Al/MgAl2O4 and Ag/MgAl2O4

Ab-initio density functional calculations were performed on the geometric and the electronic structures of coherent cube-on-cube interfaces between spinel (MgAl2O4) and the two metals Al and Ag. The calculations were carried out in the local density approximation (LDA) employing norm-conserving pseudopotentials and a mixed basis set of plane waves and local orbitals. The cohesive properties of the bulk materials are determined in good agreement with experiment. Four different high-symmetry translation states between the metal atoms and an Al–O or a Mg termination layer of the spinel are investigated at the unrelaxed interface distance. For Al a marked preference for the on-top O position on the Al–O layer is found, whereas for Ag the hollow-site positions are slightly preferred over the on-top O position on the Al–O layer. An optimization of the interface distance yields a distinct energy minimum at 1.90 Å for Al/MgAl2O4 on the on-top O site, in very good agreement with experiment. For Ag the total-energy curves of the different adhesion sites intersect and enable a low-energy dissociation path.

Evolution of the folding ability of proteins through functional selection.

An evolutionary process is simulated with a simple spin-glass-like model of proteins to examine the origin of folding ability. At each generation, sequences are randomly mutated and subjected to a simulation of the folding process based on the model. According to the frequency of local configurations at the active sites, sequences are selected and passed to the next generation. After a few hundred generations, a sequence capable of folding globally into a native conformation emerges. Moreover, the selected sequence has a distinct energy minimum and an anisotropic funnel on the energy surface, which are the imperative features for fast folding of proteins. The proposed model reveals that the functional selection on the local configurations leads a sequence to fold globally into a conformation at a faster rate.

Semi-empirical molecular orbital calculations on the interaction between singlet oxygen and amines: modeling charge transfer quenching

Semi-empirical molecular orbital calculations were performed using MINDO/3 to examine the mechanism of quenching of singlet (excited) molecular oxygen by amines. Amines with reported ionization potentials and singlet oxygen quenching rate constants were modeled with singlet oxygen at various distances from the amine nitrogen, and the enthalpies of formation of the resultant supramolecules were graphed vs. the nitrogen-oxygen separation. Primary amines gave a distinct energy minimum at a nitrogen-oxygen separation of about 1.54 Å and a nitrogen-oxygen-oxygen “bond” angle of about 119°. The electron density at nitrogen and the distal oxygen in the minimum energy complex, relative to that in the individual molecules, indicated a substantial (approximately 0.3 esu) transfer of charge from nitrogen to oxygen, consistent with a charge transfer complex. Secondary amines showed a less distinct energy minimum at the same nitrogen-oxygen separation, whereas tertiary amines gave only an inflection point. Because a charge transfer quenching mechanism requires intersystem crossing (singlet to triplet) during complexation, the upper limit of the energy of the charge transfer complex was also calculated by specifying a triplet state. This was substantially higher in energy than the singlet complex in the case of primary and secondary amines, but slightly lower in energy for tertiary amines. This calculated upper limit for the enthalpy of activation of intersystem crossing (quenching) via a charge transfer complex correlated well ( r = −0.97) with the logarithm of the quenching rate constant for a series of amines. The close proximity (1.54 Å) required between nitrogen and oxygen in the charge transfer complex explains the sensitivity to steric hindrance in the vicinity of nitrogen observed for singlet oxygen quenching rates by aliphatic amines. These data are consistent with a charge transfer mechanism of quenching of singlet oxygen by amines.

The ground state of MoCr(O2CH)4 at theab initio SCF and CI levels. A symmetry adapted RHF energy functional with an artificial double minimum

Ab initio restricted Hartree-Fock (RHF) calculations carried out on the ground state of MoCr(O2CH)4 lead to two distinct energy minima according to the initial guess made for the set of trial vectors. It is shown that these two symmetry-adapted wavefunctions can be correlated with a twofold degenerate broken-symmetry solution previously characterized for the related system of higher symmetry Cr2(O2CH)4. Complete CI expansions have been carried out from either RHF polarized wavefunction using as a basis the set of eight frontier MO's with high metal character. These expansions yield poorly resymmetrized wavefunctions. A similar CI expansion has finally been carried out from a wavefunction resymmetrized at the SCF level and corresponding to a saddle point of the RHF energy hypersurface. The total energy associated with this latter expansion is the lowest obtained in the present work. The natural orbital analysis corresponds to (σ)1.86(π)3.58(δ)1.54(δ)0.46(π)0.42 (δ*)0.14 and shows that this resymmetrized CI expansion is in many respects similar to the correlated wavefunctions obtained for the homobinuclear parent systems.

Molecular fragmentations: Part VIII. Structures and energies of mass spectral fragments derived from tetraphosphorus trisulphide

Molecular structures and energies have been calculated in the MNDO approximation, for P 4S 3 and its molecular ion P 4S 3 +, and for the mass spectral fragment pairs: (P 3S 3 + + P), (P 3S 2 + + PS), (P 3S + + PS 2), (P 2S 3 + + P 2), (P 2S 2 + + P 2S), (P 2S + + P 2S 2), (P 2S 2), PS 3 + + P 3), (PS 2 + + P 3S), (PS + + P 3S 2), and (PS + + P 2S + PS). Three distinct energy minima were found for each of P 2S 2 + and P 2S 2, and two minima for each of P 2S +, P 2S, PS 3 +, PS 3 +, PS 2 +, PS 2, P 3 + and P 3. The fragments arising from P 4 and P 4 + were also investigated. The structures are discussed in terms of the Jahn—Teller effect, whose predictions are fulfilled without exception.

Analytic configuration interaction gradient studies of SH4, sulfurane

The potential energy surface of SH4, the prototype sulfurane, has been examined in light of previous theoretical studies suggesting that there may be two distinct energy minima. The first of these has the four H atoms in roughly octahedral positions, as in the experimentally known SF4 molecule, and belongs to point group C2v. The second isomer is square pyramidal, point group C4v. Molecular electronic structure theory has been applied using basis sets of triple zeta (TZ) and triple zeta plus polarization (TZ+P) quality. Configuration interaction (CI) including in some cases all single and double excitations was carried out and geometries optimized via newly developed analytic CI gradient techniques. At the TZ SCF and TZ CI levels of theory there are both C2v and C4v relative minima, separated by +2.4 and −1.6 kcal, respectively. However, using the more complete TZ+P SCF and TZ+ P CI methods, the C2v minimum disappears, leaving only the C4v minimum. Geometries corresponding to the expected C2v minimum lie about 6 kcal above the square pyramid structure. The C4v mimimum lies 74.6 kcal above separated H2S+H2 at the TZ+ P CI level of theory, and this is reduced to 72.4 kcal when the effects of higher excitations (unlinked clusters) are considered. Harmonic vibrational frequencies have been predicted at the three simpler levels of theory to prove the proposed designations of the various stationary points. For the square pyramidal SH4, the predicted frequencies are quite sensitive to basis set, as might be expected for an extremely flat potential energy surface such as this. The square planar geometry lies only slightly above the square pyramid, which faces a barrier of 2.3 kcal to inversion. The transition state for dissociation via SH4→SH2+H2 was also located at several levels of theory and has an interesting structure. The barrier to dissociation is ∼46 kcal and the activation energy ∼42 kcal, suggesting that SH4 should be a ’’makable’’ molecule.