Optimization of CHARMM force field parameters for ryanodine receptor inhibitory drug dantrolene using FFTK and FFParam.

CONTEXT: Ryanodine receptors (RyRs) are large intracellular ligand-gated calcium release ion channels. Mutations in human RyR1 in combination with a volatile anesthetic or muscle relaxant are known to cause leaky RyRs resulting in malignant hyperthermia (MH). This has long been primarily treated with the RyR inhibitory drug dantrolene. Alternatives to dantrolene as a RyR inhibitor may be found through computer-aided drug design. Additionally, molecular dynamics (MD) studies of dantrolene interacting with RyRs may reveal its full mechanism of action. The availability of accurate force field parameters is important for the success of both. METHODS: In this study, force field parameters for dantrolene were obtained from the CHARMM General Force Field (CGenFF) program and optimized using the force field toolkit (FFTK) and FFParam programs. The obtained parameters were then validated by a comparison between calculated and experimental IR spectra and normal mode analysis, among other techniques.

NICE-FF: A non-empirical, intermolecular, consistent, and extensible force field for nucleic acids and beyond.

A new non-empirical ab initio intermolecular force field (NICE-FF in buffered 14-7 potential form) has been developed for nucleic acids and beyond based on the dimer interaction energies (IEs) calculated at the spin component scaled-MI-second order Møller-Plesset perturbation theory. A fully automatic framework has been implemented for this purpose, capable of generating well-polished computational grids, performing the necessary ab initio calculations, conducting machine learning (ML) assisted force field (FF) parametrization, and extending existing FF parameters by incorporating new atom types. For the ML-assisted parametrization of NICE-FF, interaction energies of ∼18 000 dimer geometries (with IE < 0) were used, and the best fit gave a mean square deviation of about 0.46 kcal/mol. During this parametrization, atom types apparent in four deoxyribonucleic acid (DNA) bases have been first trained using the generated DNA base datasets. Both uracil and hypoxanthine, which contain the same atom types found in DNA bases, have been considered as test molecules. Three new atom types have been added to the DNA atom types by using IE datasets of both pyrazinamide and 9-methylhypoxanthine. Finally, the last test molecule, theophylline, has been selected, which contains already-fitted atom-type parameters. The performance of NICE-FF has been investigated on the S22 dataset, and it has been found that NICE-FF outperforms the well-known FFs by generating the most consistent IEs with the high-level ab initio ones. Moreover, NICE-FF has been integrated into our in-house developed crystal structure prediction (CSP) tool [called FFCASP (Fast and Flexible CrystAl Structure Predictor)], aiming to find the experimental crystal structures of all considered molecules. CSPs, which were performed up to 4 formula units (Z), resulted in NICE-FF being able to locate almost all the known experimental crystal structures with sufficiently low RMSD20 values to provide good starting points for density functional theory optimizations.

Stable and metastable crystal structures and ammonia dynamics in strontium chloride ammines.

Metal halide ammines are promising ammonia storage materials due to their high ammonia densities and suitable decomposition properties. Here, we studied the polymorphism of ammines with a general formula of Sr(NH3)nCl2 (n = 1, 2, 4, 6, and 8) by combining the Fast and Flexible CrystAl Structure Predictor (FFCASP) with density functional theory (DFT) calculations. Furthermore, the lattice stability and the minimum energy paths for bulk and surface diffusion of NH3 were investigated by performing phonon and nudged elastic band (NEB) calculations. In addition to the successful reproduction of the reported experimental crystal structures of octammine (Pnma (IT number 62)), diammine (Aem2 (IT number 39)) and monoammine (Cmcm (IT number 63)), several isoenergetic polymorphs for each phase were also found. Not only the experimentally determined octammine and monoammine structures, but also the proposed structures for the hexammine and tetrammine phases were found to be metastable. While phonon calculations show instability for the experimental diammine structure, some of the proposed structures for the diammine phase showed thermodynamical stability. Moreover, NEB paths examining the bulk and surface diffusion of NH3 are in accordance with the experimental desorption enthalpies.

Optimization of PLGA-DSPE hybrid nano-micelles with enhanced hydrophobic capacity for curcumin delivery.

Poly (D, L Lactic-co-Glycolic acid) (PLGA) is an FDA-approved polymer. It is distinguished from other biocompatible polymers by its feasibility of production and safety for intravenous cancer tumor targeting. Curcumin (CUR) is a natural molecule with versatile bioactivities including inhibiting the nuclear Factor kappa B (Nf-kB) levels in cancer cells, increased by chemotherapy agents. Our group previously reported a successful decrease in the p65 (RelA) subunit of Nf-kB using 125 µg/ml CUR loaded into PLGA nano-micelles. However, this amount was insufficient to reduce all Nf-kB subunits. This study aimed to increase the hydrophobic capacity of PLGA toward CUR using 1,2-Distearoyl-sn-glycerol-3-phosphoethanolamine (DSPE), an FDA-approved phospholipid. PLGA-DSPE hybrid nano-micelles (HNM) were prepared using two different methods, oil-in-water (OiWa) and film preparation-rehydration (FiRe). The encapsulated CUR was successfully increased to 250 µg/ml using the FiRe method. Physicochemical characterization of CUR-loaded HNM was performed using DLS FT-IR, DSC, and HPLC. In HNM with a size of 156.6 nm, DSPE, incorporated with all functional groups of PLGA, and CUR was trapped in the core of this structure. The release profile of CUR was suitable for targeted cancer therapy and the Encapsulation Efficacy was 92%.

Equiatomic binary phases of Copper-Rare Earth Elements. An overview of monocuprides from first-principles calculations.

Equiatomic binary phases of copper with rare earth (RE) elements exhibit either primitive cubic ( P m 3 ‾ m ${Pm\bar 3m}$ ) or orthorhombic (Pnma) structures and in some cases both. By using density functional theory (DFT), we calculated the enthalpies of formation along the series of RE elements combined equimolarly with copper. For RE from Sc to Lu, the calculated enthalpies of formation fall in the range -49.8 kJ/mol for LuCu to -9.1 kJ/mol for the least thermodynamically stable CeCu. Except NdCu, all the other cubic or orthorhombic compounds exhibit lattice stability. Either forms of NdCu indicated lattice instability. Along the Sc-group, the hypothetical primitive cubic and orthorhombic forms of LuCu are found thermodynamically and mechanically stable. The overall trend of the formation enthalpies as a function of the Meyer Periodic Number is consistent with the energy trend of the 4 f-orbital filling as moving from Sc to Lu monocuprides. In addition, the calculated Gibbs free energies indicate that the thermodynamic stability is largely due to the entropic contributions. All standard DFT calculations were also repeated with DFT+U to better describe the correlation between the 5d-4f and 3d shells of RECu compounds. It has been found that DFT+U slightly affects the enthalpies of formation of RECu binaries. Moreover, DFT+U shifts up the f-band energies of RECu with light RE elements (such as La, Ce and Pr) and in contrast lowers them in the case of RECu with heavy RE elements from Nd to Lu.

Enhancing the Kinetic Stability of Polymeric Nanomicelles (PLGA) Using Nano-Montmorillonite for Effective Targeting of Cancer Tumors.

The toxic profile of chemical cross-linkers used in enhancing the stability of self-assembled nanomicelles made of amphiphilic polymeric materials hinders their use in clinical applications. This study was aimed to use the layered structure of Na-montmorillonite (MMT) as a stabilizer for nanomicelles made of poly(d,l-lactide-co-glycolide) (PLGA) amphiphilic polymer. The size of Na-MMT was reduced below 40 nm (nano-MMT) by processing in an attritor prior to its incorporation with PLGA. Hybrid PLGA nano-MMT (PM) nanoparticles (NPs) were prepared using dialysis nanoprecipitation. The size distribution was measured using dynamic light scattering (DLS). Loading 1250 µg of the model drug molecule curcumin to PM (PMC) resulted in obtaining 88 nm-sized particles, suitable for passive targeting of cancer tumors. The structure of nano-MMT and its position in PMC were investigated using FT-IR, differential scanning chalorimetry (DSC), XRF, XRD, ESEM, and EDAX assays, all of which showed the exfoliated structure of nano-MMT incorporated with both hydrophilic and hydrophobic blocks of PLGA. Curcumin was mutually loaded to PLGA and nano-MMT. This firm incorporation caused a serious extension in the release of curcumin from PMC compared to PLGA (PC). Fitting the release profile to different mathematical models showed the remarkable role of nano-MMT in surface modification of PLGA NPs. The ex vivo dynamic model showed the enhanced stability of PMC in simulated blood flow, while cytotoxicity assays showed that nano-MMT does not aggravate the good toxic profile of PLGA but improves the anticancer effect of payload. Nano-MMT could be used as an effective nontoxic stabilizer agent for self-assembled NPs.

FFCASP: A Massively Parallel Crystal Structure Prediction Algorithm.

A new algorithm called Fast and Flexible CrystAl Structure Predictor (FFCASP) was developed to predict the structure of covalent and molecular crystals. FFCASP is massively parallel and able to handle more than 200 atoms in the unit cell (in other terms, it allows global optimization around 100 individual parameters). It uses a global optimizer specialized for Crystal Structure Prediction (CSP) which combines particle swarm and simulated annealing optimizers. Three different molecular crystals, including diverse intermolecular interactions, namely, cytosine, coumarin, and pyrazinamide, have been selected to evaluate the performance of FFCASP. While cytosine polymorphs have been searched by employing two different force fields (a DFT-SAPT based intermolecular potential and generalized amber force field (GAFF)) up to Z = 16, only GAFF has been used both in coumarin and pyrazinamide polymorph searches up to Z = 4. For these three molecular crystals, FFCASP generated more than 20 000 crystal structures, and the unique ones have been further treated by DFT-D3. A combination of data mining and a machine learning approach was introduced to determine the unique structures and their distribution into different clusters, which ultimately gives an opportunity to retrieve the common features and relations between the resulting structures. There are two known experimental crystal structures of cytosine, and both were successfully located with FFCASP. Two of the reported crystal structures of coumarin have been reproduced. Similarly, in pyrazinamide, three known experimental structures have been rediscovered. In addition to finding the experimentally known structures, FFCASP also located other low-energy structures for each considered molecular crystals. These successes of FFCASP offer the possibility to discover the polymorphic nature of other important molecular crystals (e.g., drugs) as well.

Towards the crystal structure of thymine: An intermolecular force field development and parallel global cluster optimizations.

A new ab initio potential for the thymine dimer has been developed by using a combination of density functional theory and symmetry-adapted perturbation theory (DFT-SAPT). It has been shown that DFT-SAPT is in very good agreement with the reference CCSD(T) calculations performed for the hydrogen-bonded and stacked thymine dimers. Parallel global cluster optimizations have been carried out employing the new force field from the dimer to n = 50. It has been observed that the resulting cluster structures tend to form the building blocks of the crystal structure of thymine. This study therefore highlights the importance of dimer potentials to gain insights about the crystal structures.

Symmetry-adapted perturbation theory potential for the adenine dimer.

A new intermolecular interaction potential for the adenine dimer has been developed with the help of a combination of symmetry-adapted perturbation theory and density functional theory (DFT-SAPT). Supermolecular intermolecular interaction energy computations on hydrogen-bonded and stacked adenine dimers at B3LYP-D, MP2, SCS-MP2, SCS-MI-MP2 and CCSD(T) levels showed that DFT-SAPT is in a very good agreement with CCSD(T). The developed ab initio intermolecular potential has been used to predict the cluster structure of adenine dimers, trimers and tetramers. These global cluster optimizations reproduced adenine dimers reported in the literature and moreover new low-energy structures were also located. For trimers and tetramers, new hydrogen-bonded and stacked low-energy structures have also been found. The current findings suggest that the new ab initio potential can further be exploited to reveal the structure and energy of much larger supramolecular adenine clusters.

The intermolecular dimer potential for guanine.

The ab initio intermolecular potential of guanine has been developed with the help of a combination of symmetry-adapted perturbation theory and density functional theory (DFT). The resulting potential has been globally optimized to locate the guanine cluster structures up to tetramers. It has been found that the new potential is able to reproduce the known guanine cluster structures, especially the guanine quartet stabilized by Hoogsteen hydrogen bonds, in addition to new low-energy conformers. The performance of the potential was also compared with the AMBER force field as well as DFT-D and MP2 levels of theory. The model potential is in agreement with the ab initio methods and it shows a better performance compared to AMBER. Therefore, it can be further exploited in molecular dynamics or global optimizations to determine the structure and energy of much larger guanine clusters.

First principles potential for the cytosine dimer.

We developed a new first principles potential for the cytosine dimer. The ab initio calculations were performed with a DFT-SAPT combination of the symmetry-adapted perturbation method and density functional theory, and fitted to a model site-site functional form. The model potential was used to predict cluster structures up to cytosine hexamers. The global cluster structure optimizations showed that the new potential is able to reproduce some of the 2D filament structures. Moreover many new non-planar cytosine cluster structures were also discovered. Interaction energies of these clusters were compared with B3LYP-D, MP2, SCS-MP2, SCS-MI-MP2 and AMBER. It has been shown that the model agrees well with all ab initio methods, especially for the cytosine hexamer. The model potential outperforms the AMBER force field and therefore it can be exploited to study more challenging larger systems.

Ab initio crystal structure prediction by combining symmetry analysis representations and total energy calculations. An insight into the structure of Mg(BH4)2.

In materials science there is an increasing need for developing a robust and reliable first-principle approach capable of predicting crystal structures, by taking only the stoichiometry as an input. We integrate several methodologies to tackle this problem including quantum chemistry cluster calculations, simulated annealing algorithm for structure modelling, density functional theory total energy calculations and symmetry group analysis. A case study is Mg(BH(4))(2) in the aim to find the reasons for discrepancies between theoretically and experimentally proposed structures. In addition to new stable monoclinic, orthorhombic and tetragonal structures, a cubic one is suggested as a possible high energy structure. Moreover, the symmetry group analysis makes possible to link symmetry-related structures via group-subgroup relations, and subsequently identify local minima on the Potential Energy Surface.

Towards a spectroscopic and theoretical identification of the isolated building blocks of the benzene-acetylene cocrystal.

Isomer- and mass-selective UV and IR-UV double resonance spectra of the BA3, B2A, and B2A2 clusters of benzene (B) and acetylene (A) are presented. Cluster structures are assigned by comparison with the UV and IR spectra of benzene, the benzene dimer, as well as the BA, BA2, and B2A clusters. The intermolecular vibrations of BA are identified by dispersed fluorescence spectroscopy. Assignment of the cluster structures is supported by quantum chemical calculations of IR spectra with spin-component scaled second-order Møller-Plesset (SCS-MP2) theory. Initial propositions for various structures of the BA3 and B2A2 aggregates are generated with model potentials based on density functional theory combined with the symmetry-adapted perturbation theory (DFT-SAPT) approach. Shape and relative cluster stabilities are then confirmed with SCS-MP2. T-shaped geometries are the dominant structural motifs. Higher-energy isomers are also observed. The detected cluster structures are correlated with possible cluster formation pathways and their role as crystallization seeds is discussed.

Lithium dihydroborate: first-principles structure prediction of LiBH2.

We report a first-principles structure prediction of the LiBH(2), which structures are modeled by using four formula units per unit cell without symmetry restrictions. The computational methodology combines a simulated annealing approach and density functional total energy calculations for crystalline solid structures. The predicted lowest energy structure shows the formation of linear anionic chains, (∞)(1)[BH(2)], enthalpy of formation at 0 K equal to -90.07 kJ/mol. Ring structures, in particular with butterfly and planar square topologies, are found to be stable but well above the ground state by 20.26 and 12.92 kJ/mol, respectively. All convergent structures fall in the symmetry families monoclinic, tetragonal, and orthorhombic. For the representative structures of each family group, simulated X-ray diffraction patterns and infrared spectra are reported.

First principles potential for the acetylene dimer and refinement by fitting to experiments.

We report the definition and refinement of a new first principles potential for the acetylene dimer. The ab initio calculations were performed with the DFT-SAPT combination of symmetry-adapted intermolecular perturbation method and density functional theory, and fitted to a model site-site functional form. Comparison of the calculated microwave spectrum with experimental data revealed that the barriers to isomerization were too low. This potential was refined by fitting the model parameters in order to reproduce the observed transitions, an excellent agreement within ~1 MHz being achieved.

A multifaceted approach to hydrogen storage.

The widespread adoption of hydrogen as an energy carrier could bring significant benefits, but only if a number of currently intractable problems can be overcome. Not the least of these is the problem of storage, particularly when aimed at use onboard light-vehicles. The aim of this overview is to look in depth at a number of areas linked by the recently concluded HYDROGEN research network, representing an intentionally multi-faceted selection with the goal of advancing the field on a number of fronts simultaneously. For the general reader we provide a concise outline of the main approaches to storing hydrogen before moving on to detailed reviews of recent research in the solid chemical storage of hydrogen, and so provide an entry point for the interested reader on these diverse topics. The subjects covered include: the mechanisms of Ti catalysis in alanates; the kinetics of the borohydrides and the resulting limitations; novel transition metal catalysts for use with complex hydrides; less common borohydrides; protic-hydridic stores; metal ammines and novel approaches to nano-confined metal hydrides.

Constructing simple yet accurate potentials for describing the solvation of HCl/water clusters in bulk helium and nanodroplets.

The infrared spectroscopy of molecules, complexes, and molecular aggregates dissolved in superfluid helium clusters, commonly called HElium NanoDroplet Isolation (HENDI) spectroscopy, is an established, powerful experimental technique for extracting high resolution ro-vibrational spectra at ultra-low temperatures. Realistic quantum simulations of such systems, in particular in cases where the solute is undergoing a chemical reaction, require accurate solute-helium potentials which are also simple enough to be efficiently evaluated over the vast number of steps required in typical Monte Carlo or molecular dynamics sampling. This precludes using global potential energy surfaces as often parameterized for small complexes in the realm of high-resolution spectroscopic investigations that, in view of the computational effort imposed, are focused on the intermolecular interaction of rigid molecules with helium. Simple Lennard-Jones-like pair potentials, on the other hand, fall short in providing the required flexibility and accuracy in order to account for chemical reactions of the solute molecule. Here, a general scheme of constructing sufficiently accurate site-site potentials for use in typical quantum simulations is presented. This scheme employs atom-based grids, accounts for local and global minima, and is applied to the special case of a HCl(H(2)O)(4) cluster solvated by helium. As a first step, accurate interaction energies of a helium atom with a set of representative configurations sampled from a trajectory following the dissociation of the HCl(H(2)O)(4) cluster were computed using an efficient combination of density functional theory and symmetry-adapted perturbation theory, i.e. the DFT-SAPT approach. For each of the sampled cluster configurations, a helium atom was placed at several hundred positions distributed in space, leading to an overall number of about 400,000 such quantum chemical calculations. The resulting total interaction energies, decomposed into several energetic contributions, served to fit a site-site potential, where the sites are located at the atomic positions and, additionally, pseudo-sites are distributed along the lines joining pairs of atom sites within the molecular cluster. This approach ensures that this solute-helium potential is able to describe both undissociated molecular and dissociated (zwitter-) ionic configurations, as well as the interconnecting reaction pathway without re-adjusting partial charges or other parameters depending on the particular configuration. Test calculations of the larger HCl(H(2)O)(5) cluster interacting with helium demonstrate the transferability of the derived site-site potential. This specific potential can be readily used in quantum simulations of such HCl/water clusters in bulk helium or helium nanodroplets, whereas the underlying construction procedure can be generalized to other molecular solutes in other atomic solvents such as those encountered in rare gas matrix isolation spectroscopy.

First-principles determination of the ground-state structure of LiBH4.

The potential energy surface of LiBH4 is investigated by a ground-state search method based on simulated annealing and first-principles density functional theory calculations. A new stable orthogonal structure with Pnma symmetry is found, which is 9.66 kJ/mol lower in energy than the proposed Pnma structure by Soulié et al. [J. Alloys Compd. 346, 200 (2002)]. For the high-temperature structure, we suggest a new monoclinic P2/c structure, which is 21.26 kJ/mol over the ground-state energy and shows no lattice instability.

How accurate is the density functional theory combined with symmetry-adapted perturbation theory approach for CH-pi and pi-pi interactions? A comparison to supermolecular calculations for the acetylene-benzene dimer.

Five different orientations of the acetylene-benzene dimer including the T-shaped global minimum structure are used to assess the accuracy of the density functional theory combined with symmetry adapted perturbation theory (DFT-SAPT) approach in its density-fitting implementation (DF-DFT-SAPT) for the study of CH-pi and pi-pi interactions. The results are compared with the outcome of counterpoise corrected supermolecular calculations employing second-order Møller-Plesset (MP2), spin-component scaled MP2 (SCS-MP2) and single and double excitation coupled cluster theory including perturbative triple excitations (CCSD(T)). For all considered orientations MP2 predicts much deeper potential energy curves with considerably shifted minima compared to CCSD(T) and DFT-SAPT. In spite of being an improvement over the results of MP2, SCS-MP2 tends to underestimate the well depth while DFT-SAPT, employing an asymptotically corrected hybrid exchange-correlation potential in conjunction with the adiabatic local density approximation for the exchange-correlation kernel, is found to be in excellent agreement with CCSD(T). Furthermore, DFT-SAPT provides a detailed understanding of the importance of the electrostatic, induction and dispersion contributions to the total interaction energy and their repulsive exchange corrections.