Parameterization of peptide 13C carbonyl chemical shielding anisotropy in molecular dynamics simulations.

NMR chemical shielding anisotropy (CSA) relaxation is an important tool in the study of dynamical processes in proteins and nucleic acids in solution. Herein, we investigate how dynamical variations in local geometry affect the chemical shielding anisotropy relaxation of the carbonyl carbon nucleus, using the following protocol: 1) Using density functional theory, the carbonyl (13)C' CSA is computed for 103 conformations of the model peptide group N-methylacetamide (NMA). 2) The variations in computed (13)C' CSA parameters are fitted against quadratic hypersurfaces containing cross terms between the variables. 3) The predictive quality of the CSA hypersurfaces is validated by comparing the predicted and de novo calculated (13)C' CSAs for 20 molecular dynamics snapshots. 4) The CSA fluctuations and their autocorrelation and cross correlation functions due to bond-length and bond-angle distortions are predicted for a chemistry Harvard molecular mechanics (CHARMM) molecular dynamics trajectory of Ca(2+)-saturated calmodulin and GB3 from the hypersurfaces, as well as for a molecular dynamics (MD) simulation of an NMA trimer using a quantum mechanically correct forcefield. We find that the fluctuations can be represented by a 0.93 scaling factor of the CSA tensor for both R(1) and R(2) relaxations for residues in helix, coil, and sheet alike. This result is important, as it establishes that (13)C' relaxation is a valid tool for measurement of interesting dynamical events in proteins.     

室温熔盐二(三氟甲基磺酸酰)亚胺锂-尿素体系的分子动力学模拟

应用分子动力学模拟了25 ℃和50 ℃时新型室温熔盐二(三氟甲基磺酸酰)亚胺锂[LiN(SO2CF3)2, LiTFSI]与尿素(摩尔比为1:3.6)体系的结构与动力学性质. 在两个温度下体系的微观结构基本相同, Li+的配位数约为5, 且都是与溶剂和阴离子中的氧原子发生配位. 对TFSI-的研究表明, 每个TFSI-只提供四个氧中的一个与Li+配位; 而且在Li+的配位层中, TFSI-具有顺、反和gauche 等不同的构象, 并且不同构象出现的几率会随着温度的改变而改变.     

Incorporating the effect of ionic strength in free energy calculations using explicit ions

The incorporation of explicit ions to mimic the effect of ionic strength or to neutralize the overall charge on a system in free energy calculations using molecular dynamics simulations is investigated. The difference in the free energy of hydration between two triosephosphate isomerase inhibitors calculated at five different ion concentrations is used as an example. We show that the free energy difference can be highly sensitive to the presence of explicit ions even in cases where the mutation itself does not involve a change in the overall charge. The effect is most significant if the molecule carries a net charge close to the site mutated. Furthermore, it is shown that the introduction of a small number of ions can lead to very severe sampling problems suggesting that in practical calculations convergence can best be achieved by incorporating either no counterions or by simulating at high ionic strength to ensure sufficient sampling of the ion distribution.     

Binding Ensembles of p53-MDM2 Peptide Inhibitors by Combining Bayesian Inference and Atomistic Simulations

Designing peptide inhibitors of the p53-MDM2 interaction against cancer is of wide interest. Computational modeling and virtual screening are a well established step in the rational design of small molecules. But they face challenges for binding flexible peptide molecules that fold upon binding. We look at the ability of five different peptides, three of which are intrinsically disordered, to bind to MDM2 with a new Bayesian inference approach (MELD × MD). The method is able to capture the folding upon binding mechanism and differentiate binding preferences between the five peptides. Processing the ensembles with statistical mechanics tools depicts the most likely bound conformations and hints at differences in the binding mechanism. Finally, the study shows the importance of capturing two driving forces to binding in this system: the ability of peptides to adopt bound conformations (ΔGconformation) and the interaction between interface residues (ΔGinteraction).     

A computational model of the nicotinic acetylcholine binding site

We have derived a model of the nicotinic acetylcholine binding site. This was accomplished by using three known agonists (acetylcholine, nicotine and epibatidine) as templates around which polypeptide side chains, found to be part of the receptor cavity from published molecular biology studies, are allowed to flow freely in molecular dynamics simulations and mold themselves around these templates. The resulting supramolecular complex should thus be a complement, both in terms of steric effects as well as electronic effects, to the agonists and it should be a good estimation of the true receptor cavity structure. The shapes of those minireceptor cavities equilibrated rapidly on the simulation time scale and their structural congruence is very high, implying that a satisfactory model of the nicotinic acetylcholine binding site has been achieved. The computational methodology was internally tested against two rigid and specific antagonists (dihydro--erytroidine and erysoidine), that are expected to give rise to a somewhat differently shaped binding site compared to that derived from the agonists. Using these antagonists as templates there were structural reorganizations of the initial receptor cavities leading to distinctly different cavities compared to agonists. This indicates that adequate times and temperatures were used in our computational protocols to achieve equilibrium structures for the agonists. Overall, both minireceptor geometries for agonists and antagonists are similar with the exception of one amino acid (ARG209).     

受限于纳米碳管中的乙醇分子的结构和扩散的分子模拟研究

利用分子模拟研究了常温常压下受限于(8,8) (管径1.081 nm)和(15,15) (管径 2.035 nm)单壁纳米碳管中的乙醇分子. 对受限分子的径向密度分布和氢键等静态性质以及扩散性质进行了分析. 结果显示在管内乙醇分子的平均氢键数目和主体相一致. 乙醇分子在(8,8)碳管内具有高度有序的结构, 而在(15,15)碳管内由于空间的增大导致结构有序度的降低, 其中分子取向已呈随机分布. 进一步对扩散系数的分析发现, 在管内乙醇分子的轴向扩散系数低于主体相, 特别在(8,8)碳管内乙醇分子几乎丧失了轴向扩散能力.     

Solvation of uranyl(II), europium(III) and europium(II) cations in "basic" room-temperature ionic liquids: a theoretical study

We report a molecular dynamics study of the solvation of UO2(2+), Eu3+ and Eu2+ ions in two "basic" (Lewis acidity) room-temperature ionic liquids (IL) composed of the 1-ethyl-3-methylimidazolium cation (EMI+) and a mixture of AlCl4- and Cl- anions, in which the Cl-/AlCl4- ratio is about 1 and 3, respectively. The study reveals the importance of the [UO2Cl4]2- species, which spontaneously form during most simulations, and that the first solvation shell of europium is filled with Cl- and AlCl4- ions embedded in a cationic EMI+ shell. The stability of the [UO2Cl4]2- and [Eu(III)Cl6]3- complexes is supported by quantum mechanical calculations, according to which the uranyl and europium cations intrinsically prefer Cl- to the AlCl4- ion. In the gas phase, however, [Eu(III)Cl6]3- and [Eu(II)Cl6]4- complexes are predicted to be metastable and to lose two to three Cl- ions. This contrasts with the results of simulations of complexes in ILs, in which the "solvation" of the europium complexes increases with the number of coordinated chlorides, leading to an equilibrium between different chloro species. The behavior of the hydrated [Eu(OH2)8]3+ complex is considered in the basic liquids; the complex exchanges H2O molecules with Cl- ions to form mixed [EuCl3(OH2)4] and [EuCl4(OH2)3]- complexes. The results of the simulations allow us to better understand the microscopic nature and solvation of lanthanide and actinide complexes in "basic" ionic liquids.     

A Photophysical Study of Terphenyl Core Oligosulfonimide Dendrimers Exhibiting High Steady‐State Anisotropy

The photophysical properties of three dendrimers containing a p‐terphenyl core with appended sulfonimide branches of different size and n‐octyl chains have been investigated in dichloromethane solution. In the dendrimer absorption spectra contributions from both the branches and the core are clearly identified. The fluorescence spectra show only the characteristic fluorescence of the terphenyl unit. Energy transfer from the appended chromophoric groups to the core does not occur. In the dendrimers, the terphenyl core exhibits a very high fluorescence quantum yield (ca. 0.75) and a short emission lifetime (0.8 ns). These properties allowed investigations of the fluorescence depolarization caused by rotation of the dendrimers. The dendrimers show a very high steady‐state anisotropy in dichloromethane solution at room temperature (0.24 for the largest one), compared to that of the parent terphenyl under the same experimental conditions (<0.01) and in rigid matrix (0.33). Both the n‐octyl chains and the sulfonimide branches play important roles to slow down the molecular rotation.     

Lithium bromide in acetonitrile: Thermodynamics,theory, and simulation

A variety of methods has been used for the study of lithium bromide solutions in acetonitrile yielding by their combination reliable information on different levels of approximation. Osmotic coefficients based on precise vapor pressure measurements are reproduced by CM (chemical model) and HNC (hypernetted chain) calculations and by BD (brownian dynamics) simulations. The results of neutron scattering experiments are treated with the help of HNC and BD methods. Hartree-Fock calculations on isolated LiBr pairs and solvated lithium ions yield reliable particle distances and reveal the geometry of the lithium solvation sphere.     

A force field study of diacetylene molecule by kinetic constant method

The potential constants of diacetylene molecule has been evaluated using kinetic constants. The other molecular constants such as the generalised vibrational mean amplitudes, shrinkage constants, Coriolis coupling constants and centrifugal distortion constants are also calculated using the vibrational frequencies and the results discussed.