Studying the Cu binding sites in the PrP N-terminal region: a test case for ab initio simulations

First principle ab initio molecular dynamics simulations of the Car-Parrinello type have proved to be of invaluable help in understanding the microscopic mechanisms of chemical bonding both in solid state physics and in structural biophysics. In this work we present as a test case a study of the Cu coordination mode at the Prion Protein binding sites localized in the N-terminal octarepeat region. Using medium size PC-clusters, we are able to deal with systems with up to about 350 atoms and 10(3) electrons for as long as approximately 2 ps. With a foreseeable forthcoming scaling up of the available CPU times by a factor 10(3), one can hope to be soon able to simulate systems of biological interest of realistic size and for physical times of the order of the nanosecond.     

Pair Potentials from ab initio Calculations for use in MD Simulations of Molten Alkali Carbonates

Ab initio calculations at the Hartree-Fock SCF level have been carried out to determine the pair interaction between the alkali ions and the carbonate ion. A distinction has been made between terms in the metal ion - carbonate ion interaction which have different physical origins, such as static coulomb interaction, short-range repulsion and electronic polarization. The additivity of the pair interaction is investigated in 3-body calculations. It is shown that for these 3-body systems pairwise addition of 2-body interactions from which polarization effects have been omitted is superior to pairwise addition of the full Hartree-Fock interactions. A model potential based on these modified interactions has been constructed. Results of MD simulations show that both structural and dynamical properties are well described by these pair potentials.     

Introducing a novel method based on the imperialistic competitive algorithm to determine fluorine intermolecular potential from ab initio calculations and calculation of some properties via MD simulations

In this work, the possibility of obtaining an accurate site-site potential model suitable for use in molecular dynamics (MD) simulations of fluorine from ab initio calculations has been explored. The exploration was made on ab initio calculations. To reduce the ab initio pair potentials into a site-site potential, a higher significance was assigned to the configuration which is more stable. For this purpose, the imperialistic competitive algorithm (ICA) was implemented as a powerful optimisation tool. The calculated second virial coefficients were compared to the experimental values to test the quality of the presented intermolecular potential. The relative error for the calculated second virial coefficient ranged from 0.1 to 5.6%. MD simulations were used to evaluate the ability of the proposed intermolecular potential function. The relative error for the MD simulations ranged from 0.5 to 5.2%. The results are in good agreement with experimental data.     

Application of statistical potentials to protein structure refinement from low resolution ab initio models

Recently ab initio protein structure prediction methods have advanced sufficiently so that they often assemble the correct low resolution structure of the protein. To enhance the speed of conformational search, many ab initio prediction programs adopt a reduced protein representation. However, for drug design purposes, better quality structures are probably needed. To achieve this refinement, it is natural to use a more detailed heavy atom representation. Here, as opposed to costly implicit or explicit solvent molecular dynamics simulations, knowledge-based heavy atom pair potentials were employed. By way of illustration, we tried to improve the quality of the predicted structures obtained from the ab initio prediction program TOUCHSTONE by three methods: local constraint refinement, reduced predicted tertiary contact refinement, and statistical pair potential guided molecular dynamics. Sixty-seven predicted structures from 30 small proteins (less than 150 residues in length) representing different structural classes (alpha, beta, alpha;/beta) were examined. In 33 cases, the root mean square deviation (RMSD) from native structures improved by more than 0.3 A; in 19 cases, the improvement was more than 0.5 A, and sometimes as large as 1 A. In only seven (four) cases did the refinement procedure increase the RMSD by more than 0.3 (0.5) A. For the remaining structures, the refinement procedures changed the structures by less than 0.3 A. While modest, the performance of the current refinement methods is better than the published refinement results obtained using standard molecular dynamics.     

蛋白质结构从头预测方法研究进展

蛋白质结构从头预测是不依赖模板仅从氨基酸序列信息得到天然结构。它的关键是正确定义能量函数、精确选用计算机搜索算法来寻找能量最低值。基于此,本文系统介绍了能量函数和构象搜索策略,并列举了几种比较成功的从头预测方法,通过比较得出结论:基于统计学知识的能量函数是近年来从头预测发展的主要方向,现有从头预测的构象搜索都用到Monte Carlo法。这表明随着蛋白质结构预测研究的深入,能量函数的构建、构象搜索方法的选择、大分子蛋白质结构的从头预测等关键性问题都取得了突破性进展。     

Valence isomerization of 2-phospha-4-silabicyclo[1.1.0]butane: a high-level ab initio study

The rearrangements for 2-phospha-4-silabicyclo[1.1.0]butane, analogous to the valence isomerization of the hydrocarbons bicyclobutane, 1,3-butadiene, and cyclobutene, were studied at the (U)QCISD(T)/6-311+G**//(U)QCISD/6-31G* level of theory. The monocyclic 1,2-dihydro-1,2-phosphasiletes are shown to be the thermodynamically preferred product, in contrast to the isomerization of the hydrocarbons, which favors the 1,3-butadiene structure. Furthermore, an unprecedented direct isomerization pathway to the 1,2-dihydro-1,2-phosphasiletes was identified. This pathway is competitive with the isomerization via the open-chain butadienes and becomes favorable when electron-donating substituents are present on silicon. Figure 2-Phospha-4-silabicyclo[1.1.0]butane can isomerize directly into the more stable P,Si-cyclobutene via an unprecedented [sigma2s+sigma2a] process, which becomes favorable over the isomerization via the P,Si-butadiene when electron-donating substituents are present on silicon.     

Efficient deformation algorithm for plasmid DNA simulations

Background

Plasmid DNA molecules are closed circular molecules that are widely used in life sciences, particularly in gene therapy research. Monte Carlo methods have been used for several years to simulate the conformational behavior of DNA molecules. In each iteration these simulation methods randomly generate a new trial conformation, which is either accepted or rejected according to a criterion based on energy calculations and stochastic rules. These simulation trials are generated using a method based on crankshaft motion that, apart from some slight improvements, has remained the same for many years.

Results

In this paper, we present a new algorithm for the deformation of plasmid DNA molecules for Monte Carlo simulations. The move underlying our algorithm preserves the size and connectivity of straight-line segments of the plasmid DNA skeleton. We also present the results of three experiments comparing our deformation move with the standard and biased crankshaft moves in terms of acceptance ratio of the trials, energy and temperature evolution, and average displacement of the molecule. Our algorithm can also be used as a generic geometric algorithm for the deformation of regular polygons or polylines that preserves the connections and lengths of their segments.

Conclusion

Compared with both crankshaft moves, our move generates simulation trials with higher acceptance ratios and smoother deformations, making it suitable for real-time visualization of plasmid DNA coiling. For that purpose, we have adopted a DNA assembly algorithm that uses nucleotides as building blocks.     

Lanthanide complex coordination polyhedron geometry prediction accuracies of ab initio effective core potential calculations

The ability to efficiently and accurately predict solid-state geometries of lanthanide coordination compounds efficiently and accurately is central for the design of new ligands capable of forming stable and highly luminescent complexes. Accordingly, we present in this paper a report on the capability of various ab initio effective core potential calculations in reproducing the coordination polyhedron geometries of lanthanide complexes. Starting with all combinations of HF, B3LYP and MP2(Full) with STO-3G, 3-21G, 6-31G, 6-31G* and 6-31+G basis sets for [Eu(H₂O)₉]³⁺ and closing with more manageable calculations for the larger complexes, we computed the fully predicted ab initio geometries for a total of 80 calculations on 52 complexes of Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Ho(III), Er(III) and Tm(III), the largest containing 164 atoms. Our results indicate that RHF/STO-3G/ECP appears to be the most efficient model chemistry in terms of coordination polyhedron crystallographic geometry predictions from isolated lanthanide complex ion calculations. Moreover, both augmenting the basis set and/or including electron correlation generally enlarged the deviations and aggravated the quality of the predicted coordination polyhedron crystallographic geometry. Our results further indicate that Cosentino et al.’s suggestion of using RHF/3-21G/ECP geometries appears to be indeed a more robust, but not necessarily, more accurate recommendation to be adopted for the general lanthanide complex case. Figure Graphical visualization of unsigned mean errors, UME(Eu-L)s, involving only the interatomic distances between the europium central ion and the oxygen atoms of the coordination polyhedron of the cation nona-aqua-europium(III) for various model chemistries, all compared to the “Cambridge Structural Database 2004” crystallographic geometry     

Energetics and possible mechanisms of ion-beam protein tritiation based on ab initio potential surfaces

Ab initio self-consistent field potential energy surfaces for the approach of T. T₂. T⁺. T⁺₃ and HeT⁺ to glycine in the gas phase have been determined and this data used to obtain insight into mechanisms of experimental ion-beam protein tritiation processes. Results of these calculations show that the ionic species T⁺, T⁺₃ and HeT⁺ can form stable adducts with glycine (Gly) and that each functions as a tritiation agent forming the complex GlyT⁺. Neutral T and T₂ experience a purely repulsive interaction with Gly and do not form an intermediate complex. These neutral species are expected to be less effective tritiation agents than the respective ions, in agreement with experimental observations. The fate of the stable GlyT⁺ complex is discussed and it is proposed that this species is neutralized by electron capture to give GlyT which spontaneously dissociates to either Gly+T or tritiated glycine (Gly^*)+H, with the latter reaction product channel favored statistically. The most likely site of exchange is predicted to be at the amine nitrogen although significance exchange is expected to occur at the α-carbon site by a somewhat more complex reaction mechanism.     

Effect of microsolvation on zwitterionic glycine: an ab initio and density functional theory study

The effect of microsolvation on zwitterionic glycine, considering both (-NH3(+)) as proton donor and (-COO(-)) as proton acceptor at correlated ab initio (MP2) level and density functional methods (B3LYP, PW91, MPW1PW91 and PBE) using 6-311++G** basis set has been reported. DFT methods have been employed so as to compare the performance/quality of different gradient-corrected correlation functionals (PW91, PBE), hybrid functionals (B3LYP, MPW1PW91) and to predict the near quantitative structural and vibrational properties, at reduced computational cost. B3LYP method outperforms among the different DFT methods for the computed hydrogen bond distances and found closer to the value obtained by correlated MP2 level, whereas MPW1PW91 and PBE methods shows very similar values but approximately 0.03 A less, compared to B3LYP method. MP2 calculation and single point CCSD(T)//MP2 calculation have been considered to decompose the interaction energy, including corrections for basis set superposition error (BSSE). Moreover, charge distribution analysis has also been carried out to understand the long raised questions, how and why the two body energies have significant contribution to the total binding energy.     

Vibrational spectral assignments of paraldehyde by ab initio and density functional methods

The FTIR and Laser-Raman spectra of paraldehyde have been recorded in the regions 4000–400 cm⁻¹ and 3500–250 cm⁻¹ respectively. Molecular electronic energy, geometrical structure, harmonic vibrational spectra, infrared intensities and Raman scattering activities have been computed at the HF/6-31G(d,p) and B3LYP/6-31G(d,p) levels of theory. The results were compared with experimental values with the help of scaling procedures. The observed wave numbers in FTIR and Laser-Raman spectra were analyzed and assigned to different normal modes of the molecule. Most of the modes have wave numbers in the expected range and are in good agreement with computed values.     

XPS and ab initio calculation of surface states of sulfide minerals: pyrite,chalcopyrite and molybdenite

Sulfide minerals contain sulphur in a large variety of coordination environments. Consequently, the S 2p XPS of various mineral surface states undergo different shifts in binding energy (BE) relative to the bulk, depending on the charge distribution on the surface. This in turn depends on the number, type and position of the atoms on the fracture surface, which is determined by the fracture mechanism.

We have investigated three sulfide minerals: pyrite (tetrahedrally-coordinated S), chalcopyrite (tetrahedrally-coordinated S) and molybdenite (layered structure with trigonally-coordinated S). Comparison of conventional with surface sensitive synchrotron XPS shows that the S 2p spectrum displays two additional doublets at lower BE than the bulk signal for pyrite, and one doublet each at lower and at higher BE for chalcopyrite. Each of these signals is derived from surface states. Molybdenite shows no additional states. A BE shift to lower (higher) BE suggests a charge increase (decrease) on the S atoms relative to those in the bulk because of higher (lower) charge screening.

We have used ab initio density functional calculations to validate this interpretation of the experimental evidence, obtaining Mulliken population analyses for the possible fracture surfaces and comparing their charge distribution with the corresponding bulk charge distribution. Our calculations support the assignments of S 2p surface contributions as follows: the lower BE peak of chalcopyrite (160.84 eV) as under-coordinated surface S states, the higher BE peak of chalcopyrite (161.88 eV) as surface S polymers, the lowest BE peak of pyrite (161.3 eV) as surface S monomers, and the next lowest BE peak of pyrite (162.0 eV) as under-coordinated surface S dimers. The absence of any surface states in molybdenite is also confirmed by the models.     

Ab initio simulations of Cu binding sites on the N-terminal region of prion protein

The human prion protein binds Cu²⁺ ions in the octarepeat domain of the N-terminal tail up to full occupancy at pH 7.4. Recent experiments have shown that the HGGG octarepeat subdomain is responsible for holding the metal bound in a square-planar configuration. By using first principle ab initio molecular dynamics simulations of the Car–Parrinello type, the coordination of copper to the binding sites of the prion protein octarepeat region is investigated. Simulations are carried out for a number of structured binding sites. Results for the complexes Cu(HGGGW)(wat), Cu(HGGG), and [Cu(HGGG)]₂ are presented. While the presence of a Trp residue and a water molecule does not seem to affect the nature of the copper coordination, high stability of the bond between copper and the amide nitrogen of deprotonated Gly residues is confirmed in all cases. For the more interesting [Cu(HGGG)]₂ complex, a dynamically entangled arrangement of the two domains with exchange of amide nitrogen bonds between the two copper centers emerges, which is consistent with the short Cu–Cu distance observed in experiments at full copper occupancy.     

The ethylene/metal(0) and ethylene/metal(I) redox system: model ab initio calculations

Ab initio calculations (coupled cluster with single and double excitations; CCSD) have been used to investigate the model redox systems ethylene:M(0) (M = Li, Na, K, Rb, Cs) and ethylene:M(I) (M = Be, Mg, Ca, Sr, Ba, Zn, Cd, Hg). Within C2v symmetry, the ground (2A1) states correspond to the charge distribution given in the title. The lowest (2B2) excited states correspond, somewhat counter intuitively, to the ethylene*-/=M(II)ion pair. These trends can be rationalized on the basis of simple electrostatic and configuration-mixing arguments that lead to two simple equations for predicting the electron-transfer energies for oxidation or reduction of the ethylene. The electron-transfer energies to the 2B2 ion pairs are dominated by the electrostatic ion-pairing energies.     

Direct ab initio dynamics studies of the hydrogen abstraction reactions of hydrogen atom with n-propyl radical and isopropyl radical

The kinetics of the hydrogen abstraction reactions of hydrogen atom with n-propyl radical and isopropyl radical were studied using the direct ab initio dynamics approach. BHandHLYP/cc-pVDZ method was employed to optimize the geometries of stationary points as well as the points on the minimum energy path (MEP). The energies of all the points for the two reactions were further refined at the QCISD(T)/cc-pVTZ level of theory. No barrier was found at the QCISD(T)/cc-pVTZ//BHandHLYP/cc-pVDZ level of theory for both reactions. The forward and reverse rate constants were evaluated with both canonical variational transition state theory (CVT) and microcanonical variational transition state theory ( VT) in the temperature range of 300–2,500 K. The fitted three-parameter Arrhenius expression of the calculated CVT rate constants at the QCISD(T)/cc-pVTZ//BHandHLYP/cc-pVDZ level of theory are k^CVT (n – C₃H₇)=1.68×10^–14 T^0.84 e^(319.5/T) cm³ molecule^–1 s^–1 and k^CVT (iso-C₃H₇)=4.99×10^–14 T^0.90 e^(159.5/T) cm³ molecule^–1 s^–1 for reactions of n-C₃H₇ + H and iso-C₃H₇ + H, respectively, which are in good agreement with available literature data. The variational effects were analysed.Figure Comparison of the calculated forward rate constants at the QCISD(T)/cc-pVTZ//BHandHLYP/cc-pVDZ level of theory and the available experimental and theoretical data of the reaction vs 1,000/T for the two reactions.     

A computer model to dynamically simulate protein folding: studies with crambin

The current work describes a simplified representation of protein structure with uses in the simulation of protein folding. The model assumes that a protein can be represented by a freely rotating rigid chain with a single atom approximating the effect of each side chain. Potentials describing the attraction or repulsion between different types of amino acids are determined directly from the distribution of amino acids in the database of known protein structures. The optimization technique of simulated annealing has been used to dynamically sample the conformations available to this simple model, allowing the protein to evolve from an extended, random coil into a compact globular structure. Many characteristics expected of true proteins, such as the sequence-dependent formation of secondary structure, the partitioning of hydrophobic residues, and specific disulfide pairing, are reproduced by the simulation, suggesting the model may accurately simulate the folding process.     

Determination of initial electron parameters by means of Monte Carlo simulations for the Siemens Artiste Linac 6 MV photon beam

AimIn this study, we investigated initial electron parameters of Siemens Artiste Linac with 6 MV photon beam using the Monte Carlo method.BackgroundIt is essential to define all the characteristics of initial electrons hitting the target, i.e. mean energy and full width of half maximum (FWHM) of the spatial distribution intensity, which is needed to run Monte Carlo simulations. The Monte Carlo is the most accurate method for simulation of radiotherapy treatments.Materials and methodsLinac head geometry was modeled using the BEAMnrc code. The phase space files were used as input file to DOSXYZnrc simulation to determine the dose distribution in a water phantom. We obtained percent depth dose curves and the lateral dose profile. All the results were obtained at 100 cm of SSD and for a 10 × 10 cm² field.ResultsWe concluded that there existed a good conformity between Monte Carlo simulation and measurement data when we used electron mean energy of 6.3 MeV and 0.30 cm FWHM value as initial parameters. We observed that FWHM values had very little effect on PDD and we found that the electron mean energy and FWHM values affected the lateral dose profile. However, these effects are between tolerance values.ConclusionsThe initial parameters especially depend on components of a linac head. The phase space file which was obtained from Monte Carlo Simulation for a linac can be used as calculation of scattering, MLC leakage, to compare dose distribution on patients and in various studies.     

Benchmarking of TASSER in the ab initio limit

A significant number of protein sequences in a given proteome have no obvious evolutionarily related protein in the database of solved protein structures, the PDB. Under these conditions, ab initio or template-free modeling methods are the sole means of predicting protein structure. To assess its expected performance on proteomes, the TASSER structure prediction algorithm is benchmarked in the ab initio limit on a representative set of 1129 nonhomologous sequences ranging from 40 to 200 residues that cover the PDB at 30% sequence identity and which adopt alpha, alpha + beta, and beta secondary structures. For sequences in the 40-100 (100-200) residue range, as assessed by their root mean square deviation from native, RMSD, the best of the top five ranked models of TASSER has a global fold that is significantly close to the native structure for 25% (16%) of the sequences, and with a correct identification of the structure of the protein core for 59% (36%). In the absence of a native structure, the structural similarity among the top five ranked models is a moderately reliable predictor of folding accuracy. If we classify the sequences according to their secondary structure content, then 64% (36%) of alpha, 43% (24%) of alpha + beta, and 20% (12%) of beta sequences in the 40-100 (100-200) residue range have a significant TM-score (TM-score > or = 0.4). TASSER performs best on helical proteins because there are less secondary structural elements to arrange in a helical protein than in a beta protein of equal length, since the average length of a helix is longer than that of a strand. In addition, helical proteins have shorter loops and dangling tails. If we exclude these flexible fragments, then TASSER has similar accuracy for sequences containing the same number of secondary structural elements, irrespective of whether they are helices and/or strands. Thus, it is the effective configurational entropy of the protein that dictates the average likelihood of correctly arranging the secondary structure elements.