Francesca Mocci

Partial Atomic Charges and Their Impact on the Free Energy of Solvation

Free energies of solvation (ΔG) in water and n‐octanol have been computed for common drug molecules by molecular dynamics simulations with an additive fixed‐charge force field. The impact of the electrostatic interactions was investigated by computing the partial atomic charges with four methods that all fit the charges from the quantum mechanically determined electrostatic potential (ESP). Due to the redistribution of electron density that occurs when molecules are transferred from gas phase to condensed phase, the polarization impact was also investigated. By computing the partial atomic charges with the solutes placed in a conductor‐like continuum, the charges were effectively polarized to take the polarization effects into account. No polarization correction term or similar was considered, only the partial atomic charges. Results show that free energies are very sensitive to the choice of atomic charges and that ΔG can differ by several kBT depending on the charge computing method. Inclusion of polarization effects makes the solutes too hydrophilic with most methods and in vacuo charges make the solutes too hydrophobic. The restrained‐ESP methods together with effectively polarized charges perform well in our test set and also when applied to a larger set of molecules. The effect of water models is also highlighted and shows that the conclusions drawn are valid for different three‐point models. Partitioning between an aqueous and a hydrophobic phase is also described better if the two environments polarization is taken into account, but again the results are sensitive to the charge calculation method. Overall, the results presented here show that effectively polarized charges can improve the description of solvating a drug‐like molecule in a solvent and that the choice of partial atomic charges is crucial to ensure that molecular simulations produce reliable results.

Insight into nucleic acid counterion interactions from inside molecular dynamics simulations is “worth its salt”

Nucleic acids are highly charged polyelectrolytes. Their interactions with counterions are of great importance for their structural stability, conformational behaviour and biological functions. Molecular modelling and simulation techniques, particularly molecular dynamics, have been highly useful for studies of interactions between DNA, water and ions at the molecular level, allowing us to explain many experimental observations, or to obtain information not accessible experimentally. In this review we focus on both atomistic and coarse-grained molecular simulation studies concerning the interactions of DNA with different types of counterions, with emphasis on recent studies, still open questions, limits of the method and possible further developments.

The structural organization of N -methyl-2-pyrrolidone + water mixtures: A densitometry, x-ray diffraction, and molecular dynamics study

A combined approach of molecular dynamics simulations, wide angle X-ray scattering experiments, and density measurements was employed to study the structural properties of N-methyl-2-pyrrolidone (NMP) + water mixtures over the whole concentration range. Remarkably, a very good agreement between computed and experimental densities and diffraction patterns was achieved, especially if the effect of the mixture composition on NMP charges is taken into account. Analysis of the intermolecular organization, as revealed by the radial and spatial distribution functions of relevant solvent atoms, nicely explained the density maximum observed experimentally.

Multiscale Simulations of Human Telomeric G-Quadruplex DNA

We present a coarse-grain (CG) model of human telomeric G-quadruplex, obtained using the inverse Monte Carlo (IMC) and iterative Boltzmann inversion (IBI) techniques implemented within the software package called MagiC. As a starting point, the 2HY9 human telomeric [3 + 1] hybrid, a 26-nucleobase sequence, was modeled performing a 1 μs long atomistic molecular dynamics (MD) simulation. The chosen quadruplex includes two kinds of loops and all possible combinations of relative orientations of guanine strands that can be found in quadruplexes. The effective CG potential for a one bead per nucleotide model has been developed from the radial distribution functions of this reference system. The obtained potentials take into account explicitly the interaction with counterions, while the effect of the solvent is included implicitly. The structural properties of the obtained CG model of the quadruplex provided a perfect match to those resulting from the reference atomistic MD simulation. The same set of interaction potentials was then used to simulate at the CG level another quadruplex topology (PDB id 1KF1 ) that can be formed by the human telomeric DNA sequence. This quadruplex differs from 2HY9 in the loop topology and G-strand relative orientation. The results of the CG MD simulations of 1KF1 are very encouraging and suggest that the CG model based on 2HY9 can be used to simulate quadruplexes with different topologies. The CG model was further applied to a higher order human telomeric quadruplex formed by the repetition, 20 times, of the 1KF1 quadruplex structure. In all cases, the developed model, which to the best of our knowledge is the first model of quadruplexes at the CG level presented in the literature, reproduces the main structural features remarkably well.

Glucose oxidase from Penicillium amagasakiense : Characterization of the transition state of its denaturation from molecular dynamics simulations

Glucose oxidase (GOx) is a flavoenzyme having applications in food and medical industries. However, GOx, as many other enzymes when extracted from the cells, has relatively short operational lifetimes. Several recent studies (both experimental and theoretical), carried out on small proteins (or small fractions of large proteins), show that a detailed knowledge of how the breakdown process starts and proceeds on molecular level could be of significant help to artificially improve the stability of fragile proteins. We have performed extended molecular dynamics (MD) simulations to study the denaturation of GOx (a protein dimer containing nearly 1200 amino acids) to identify weak points in its structure and in this way gather information to later make it more stable, for example, by mutations. A denaturation of a protein can be simulated by increasing the temperature far above physiological temperature. We have performed a series of MD simulations at different temperatures (300, 400, 500, and 600 K). The exit from the proteins native state has been successfully identified with the clustering method and supported by other methods used to analyze the simulation data. A common set of amino acids is regularly found to initiate the denaturation, suggesting a moiety where the enzyme could be strengthened by a suitable amino acid based modification. Proteins 2014; 82:2353–2363.

Insight into the dynamics of lanthanide-DTPA complexes as revealed by oxygen-17 NMR.

DTPA chelates of various diamagnetic and paramagnetic lanthanide(III) metal ions, as well as the chemically similar DTPA chelate of Y(3+), were studied in aqueous solution by variable temperature (17)O NMR with the aim of characterizing their internal dynamics. As a consequence of poor chemical shift dispersion and fast quadrupole relaxation, no dynamic exchange process could be detected for the diamagnetic complexes nor for the Sm-DTPA complex. In contrast, the spectra recorded for the Eu-DTPA complex show chemical exchange due to the well-known racemization process and, at high temperature, feature signal broadening that reveals a fluxional process involving the interchange of the coordinated and noncoordinated oxygen atoms of the carboxylate groups. The spectra recorded for the Pr-DTPA complex feature coalescence events due to such a fluxional process, which is ascribable to the rotation of the carboxylate groups. The activation free energy barriers determined experimentally are remarkably lower than the calculated activation barriers recently reported for the rotation of the carboxylate groups of various Ln-DOTA complexes. Furthermore, the smallest activation free energy measured for the Pr-DTPA complex, about 45 kJ mol(-1), is significantly lower than the activation free energy characterizing the racemization process. The fluxional behavior of the carboxylate groups is, however, not expected to significantly affect the residence time of the water molecule coordinated to the metal ion.

Characterization of 2,5-diaryl-1,3,4-oxadiazolines by multinuclear magnetic resonance and density functional theory calculations. Investigation on a case of very remote Hammett correlation

Two series of 2,5‐diaryl‐1,3,4‐oxadiazolines have been studied by multinuclear magnetic resonance and density functional theory calculations. A full NMR spectroscopic characterization has been performed and excellent remote Hammett correlations (σp or

Molecular Dynamics Simulation Study of Parallel Telomeric DNA Quadruplexes at Different Ionic Strengths: Evaluation of Water and Ion Models

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NMR, calorimetry, and computational studies of aqueous solutions of N-methyl-2-pyrrolidone

) have been found for para substitution in the two aryl rings through at least 11 bonds, notwithstanding the presence in the path of atoms that should act as insulators and a lack of correlation for some of the intermediate atoms. The computational investigation on the electronic delocalization, performed with the ACID (anisotropy of the induced current density) method, reveals indeed that electrons are delocalized in almost the entire molecule despite the presence of the insulators. Copyright

Dynamic NMR of low-sensitivity fast-relaxing nuclei: 17O NMR and DFT study of acetoxysilanes

Most molecular dynamics (MD) simulations of DNA quadruplexes have been performed under minimal salt conditions using the Åqvist potential parameters for the cation with the TIP3P water model. Recently, this combination of parameters has been reported to be problematic for the stability of quadruplex DNA, especially caused by the ion interactions inside or near the quadruplex channel. Here, we verify how the choice of ion parameters and water model can affect the quadruplex structural stability and the interactions with the ions outside the channel. We have performed a series of MD simulations of the human full-parallel telomeric quadruplex by neutralizing its negative charge with K(+) ions. Three combinations of different cation potential parameters and water models have been used: (a) Åqvist ion parameters, TIP3P water model; (b) Joung and Cheatham ion parameters, TIP3P water model; and (c) Joung and Cheatham ion parameters, TIP4Pew water model. For the combinations (b) and (c), the effect of the ionic strength has been evaluated by adding increasing amounts of KCl salt (50, 100, and 200 mM). Two independent simulations using the Åqvist parameters with the TIP3P model show that this combination is clearly less suited for the studied quadruplex with K(+) as counterions. In both simulations, one ion escapes from the channel, followed by significant deformation of the structure, leading to deviating conformation compared to that in the reference crystallographic data. For the other combinations of ion and water potentials, no tendency is observed for the channel ions to escape from the quadruplex channel. In addition, the internal mobility of the three loops, torsion angles, and counterion affinity have been investigated at varied salt concentrations. In summary, the selection of ion and water models is crucial as it can affect both the structure and dynamics as well as the interactions of the quadruplex with its counterions. The results obtained with the TIP4Pew model are found to be closest to the experimental data at all of the studied ion concentrations.