Mechanisms by which small molecules of diverse chemotypes arrest Sec14 lipid transfer activity.

Phosphatidylinositol (PtdIns) transfer proteins (PITPs) enhance the activities of PtdIns 4-OH kinases that generate signaling pools of PtdIns-4-phosphate. In that capacity, PITPs serve as key regulators of lipid signaling in eukaryotic cells. Although the PITP phospholipid exchange cycle is the engine that stimulates PtdIns 4-OH kinase activities, the underlying mechanism is not understood. Herein, we apply an integrative structural biology approach to investigate interactions of the yeast PITP Sec14 with small-molecule inhibitors (SMIs) of its phospholipid exchange cycle. Using a combination of X-ray crystallography, solution NMR spectroscopy, and atomistic MD simulations, we dissect how SMIs compete with native Sec14 phospholipid ligands and arrest phospholipid exchange. Moreover, as Sec14 PITPs represent new targets for the development of next-generation antifungal drugs, the structures of Sec14 bound to SMIs of diverse chemotypes reported in this study will provide critical information required for future structure-based design of next-generation lead compounds directed against Sec14 PITPs of virulent fungi.

Thermodynamic Dissection of the Intercalation Binding Process of Doxorubicin to dsDNA with Implications of Ionic and Solvent Effects.

Doxorubicin (DOX) is a cancer drug that binds to dsDNA through intercalation. A comprehensive microsecond timescale molecular dynamics study is performed for DOX with 16 tetradecamer dsDNA sequences in explicit aqueous solvent, in order to investigate the intercalation process at both binding stages (conformational change and insertion binding stages). The molecular mechanics generalized Born surface area (MM-GBSA) method is adapted to quantify and break down the binding free energy (BFE) into its thermodynamic components, for a variety of different solution conditions as well as different DNA sequences. Our results show that the van der Waals interaction provides the largest contribution to the BFE at each stage of binding. The sequence selectivity depends mainly on the base pairs located downstream from the DOX intercalation site, with a preference for (AT)2 or (TA)2 driven by the favorable electrostatic and/or van der Waals interactions. Invoking the quartet sequence model proved to be most successful to predict the sequence selectivity. Our findings also indicate that the aqueous bathing solution (i.e., water and ions) opposes the formation of the DOX-DNA complex at every binding stage, thus implying that the complexation process preferably occurs at low ionic strength and is crucially dependent on solvent effects.

Synthesis of monodisperse rod-shaped silica particles through biotemplating of surface-functionalized bacteria.

Mesoporous silica particles of controlled size and shape are potentially beneficial for many applications, but their usage may be limited by the complex procedure of fabrication. Biotemplating provides a facile approach to synthesize materials with desired shapes. Herein, a bioinspired design principle is adopted through displaying silaffin-derived 5R5 proteins on the surface of Escherichia coli by genetic manipulations. The genetically modified Escherichia coli provides a three-dimensional template to regulate the synthesis of rod-shaped silica. The silicification is initiated on the cell surface under the functionality of 5R5 proteins and subsequentially the inner space is gradually filled. Density functional theory simulation reveals the interfacial interactions between silica precursors and R5 peptides at the atomic scale. There is a large conformation change of this protein during biosilicification. Electrostatic interactions contribute to the high affinity between positively charged residues (Lys4, Arg16, Arg17) and negatively charged tetraethyl orthosilicate. Hydrogen bonds develop between Arg16 (OH), Arg17 (OH and NH), Leu19 (OH) residues and the forming silica agglomerates. In addition, the resulting rod-shaped silica copy of the bacteria can transform into mesoporous SiOx nanorods composed of carbon-coated nanoparticles after carbonization, which is shown to allow superior lithium storage performance.

Interfacial Interaction between Suolunite Crystal and Silica Binding Peptide for Novel Bioinspired Cement.

Cement and concrete have been important construction materials throughout human history. There is an urgent need to explore novel and untraditional cementitious materials to enhance the durability of building materials and structures in response to increased infrastructure demand worldwide. We report an exploratory study on a biocomposite cement based on a large-scale computational study using density functional theory. An explicitly solvated mixture of a mineral calcium silicate hydrate (C-S-H) crystal suolunite (Ca2Si2O5(OH)2·H2O) and a silicon binding peptide with amino acid sequence PRO-PRO-PRO-TRP-LEU-PRO-TYR-MET-PRO-PRO-TRP-SER is constructed using ab initio molecular dynamics (AIMD). Detailed analysis on the interface structure, interatomic bonding, mechanical properties, and solvent effect of this model reveals a complex interplay of different types of covalent and ionic bonding, including ubiquitous hydrogen bonding which plays a crucial role in their properties. The use of the total bond order density (TBOD), a single quantum mechanical metric, for assessing the interfacial cohesion for this composite biocement is proposed. We find that the solvated model has a slightly larger TBOD than the dried one. These results could lead to a systematic search and rational design for different types of bioinspired and hybrid functional materials with other inorganic minerals and organic peptides.

Molecular mechanism and binding free energy of doxorubicin intercalation in DNA.

The intercalation process of binding doxorubicin (DOX) in DNA is studied by extensive MD simulations. Many molecular factors that control the binding affinity of DOX to DNA to form a stable complex are inspected and quantified by employing continuum solvation models for estimating the binding free energy. The modified MM-PB(GB)SA methodology provides a complete energetic profile of ΔGele, ΔGvDW, ΔGpolar, ΔGnon-polar, TΔStotal, ΔGdeform, ΔGcon, and ΔGion. To identify the sequence specificity of DOX, two different DNA sequences, d(CGATCG) or DNA1 and d(CGTACG) or DNA2, with one molecule (1 : 1 complex) or two molecule (2 : 1 complex) configurations of DOX were selected in this study. Our results show that the DNA deformation energy (ΔGdeform), the energy cost from translational and rotational entropic contributions (TΔStran+rot), the total electrostatic interactions (ΔGpolar-PB/GB + ΔGele) of incorporation, the intramolecular electrostatic interactions (ΔGele) and electrostatic polar solvation interactions (ΔGpolar-PB/GB) are all unfavorable to the binding of DOX to DNA. However, they are overcome by at least five favorable interactions: the van der Waals interactions (ΔGvDW), the non-polar solvation interaction (ΔGnon-polar), the vibrational entropic contribution (TΔSvib), and the standard concentration dependent free energies of DOX (ΔGcon) and the ionic solution (ΔGion). Specifically, the van der Waals interaction appears to be the major driving force to form a stable DOX-DNA complex. We also predict that DOX has stronger binding to DNA1 than DNA2. The DNA deformation penalty and entropy cost in the 2 : 1 complex are less than those in the 1 : 1 complex, thus they indicate that the 2 : 1 complex is more stable than the 1 : 1 complex. We have calculated the total binding free energy (BFE) (ΔGt-sim) using both MM-PBSA and MM-GBSA methods, which suggests a more stable DOX-DNA complex at lower ionic concentration. The calculated BFE from the modified MM-GBSA method for DOX-DNA1 and DOX-DNA2 in the 1 : 1 complex is -9.1 and -5.1 kcal mol-1 respectively. The same quantities from the modified MM-PBSA method are -12.74 and -8.35 kcal mol-1 respectively. The value of the total BFE ΔGt-sim in the 1 : 1 complex is in reasonable agreement with the experimental value of -7.7 ± 0.3 kcal mol-1.

Impact of Hydrogen Bonding in the Binding Site between Capsid Protein and MS2 Bacteriophage ssRNA.

MS2 presents a well-studied example of a single-stranded RNA virus for which the genomic RNA plays a pivotal role in the virus assembly process based on the packaging signal-mediated mechanism. Packaging signals (PSs) are multiple dispersed RNA sequence/structure motifs varying around a central recognition motif that interact in a specific way with the capsid protein in the assembly process. Although the discovery and identification of these PSs was based on bioinformatics and geometric approaches, in tandem with sophisticated experimental protocols, we approach this problem using large-scale ab initio computation centered on critical aspects of the consensus protein-RNA interactions recognition motif. DFT calculations are carried out on two nucleoprotein complexes: wild-type and mutated (PDB IDs: 1ZDH and 5MSF ). The calculated partial charge distribution of residues and the strength of hydrogen bonding (HB) between them enabled us to locate the exact binding sites with the strongest HBs, identified to be LYS43-A-4, ARG49-C-13, TYR85-C-5, and LYS61-C-5, due to the change in the sequence of the mutated RNA.

The Hydration Effect and Selectivity of Alkali Metal Ions on Poly(ethylene glycol) Models in Cyclic and Linear Topology.

The effects of hydration and alkali metal ion (K+, Na+, Li+) bonding to two structural variants of poly(ethylene glycol) (PEG), viz., a cyclic (18-crown-6) configuration and a linear chain model with two different lengths, are studied by ab initio density functional theory calculations. A total of 24 structural models are constructed, with different conformations of the PEG chain and its molecular environment. Detailed comparisons of the results enable us to obtain conclusive evidence on the effects of the different components of the solution environment on the PEG structural variants in terms of the binding energy, partial charge distribution, solvation effect, interfacial hydrogen bonding, and cohesion between different structural units in the system composed of PEG, alkali metal ions, and water. On the basis of these comprehensive and precise comparisons, we conclude that the ion-PEG interaction is strongly influenced by the presence of solvent and that the charge transfer in the PEG complex depends crucially on its topology, the type of alkali metal ion, and the solvent. The interaction between alkali metal ions in the two PEG models does not always scale with the ion size but depends on their local environment.

Implication of the solvent effect, metal ions and topology in the electronic structure and hydrogen bonding of human telomeric G-quadruplex DNA.

We present a first-principles density functional study elucidating the effects of solvent, metal ions and topology on the electronic structure and hydrogen bonding of 12 well-designed three dimensional G-quadruplex (G4-DNA) models in different environments. Our study shows that the parallel strand structures are more stable in dry environments and aqueous solutions containing K(+) ions within the tetrad of guanine but conversely, that the anti-parallel structure is more stable in solutions containing the Na(+) ions within the tetrad of guanine. The presence of metal ions within the tetrad of the guanine channel always enhances the stability of the G4-DNA models. The parallel strand structures have larger HOMO-LUMO gaps than antiparallel structures, which are in the range of 0.98 eV to 3.11 eV. Partial charge calculations show that sugar and alkali ions are positively charged whereas nucleobases, PO4 groups and water molecules are all negatively charged. Partial charges on each functional group with different signs and magnitudes contribute differently to the electrostatic interactions involving G4-DNA and favor the parallel structure. A comparative study between specific pairs of different G4-DNA models shows that the Hoogsteen OH and NH hydrogen bonds in the guanine tetrad are significantly influenced by the presence of metal ions and water molecules, collectively affecting the structure and the stability of G4-DNA.

van der Waals Interactions on the Mesoscale: Open-Science Implementation, Anisotropy, Retardation, and Solvent Effects.

The self-assembly of heterogeneous mesoscale systems is mediated by long-range interactions, including van der Waals forces. Diverse mesoscale architectures, built of optically and morphologically anisotropic elements such as DNA, collagen, single-walled carbon nanotubes, and inorganic materials, require a tool to calculate the forces, torques, interaction energies, and Hamaker coefficients that govern assembly in such systems. The mesoscale Lifshitz theory of van der Waals interactions can accurately describe solvent and temperature effects, retardation, and optically and morphologically anisotropic materials for cylindrical and planar interaction geometries. The Gecko Hamaker open-science software implementation of this theory enables new and sophisticated insights into the properties of important organic/inorganic systems: interactions show an extended range of magnitudes and retardation rates, DNA interactions show an imprint of base pair composition, certain SWCNT interactions display retardation-dependent nonmonotonicity, and interactions are mapped across a range of material systems in order to facilitate rational mesoscale design.

Electronic structure and partial charge distribution of Doxorubicin in different molecular environments.

The electronic structure and partial charge of doxorubicin (DOX) in three different molecular environments-isolated, solvated, and intercalated in a DNA complex-are studied by first-principles density functional methods. It is shown that the addition of solvating water molecules to DOX, together with the proximity to and interaction with DNA, has a significant impact on the electronic structure as well as on the partial charge distribution. Significant improvement in estimating the DOX-DNA interaction energy is achieved. The results are further elucidated by resolving the total density of states and surface charge density into different functional groups. It is concluded that the presence of the solvent and the details of the interaction geometry matter greatly in determining the stability of DOX complexation. Ab initio calculations on realistic models are an important step toward a more accurate description of the long-range interactions in biomolecular systems.

Optical properties and electronic transitions of DNA oligonucleotides as a function of composition and stacking sequence.

The role of base pair composition and stacking sequence in the optical properties and electronic transitions of DNA is of fundamental interest. We present and compare the optical properties of DNA oligonucleotides (AT)10, (AT)5(GC)5, and (AT-GC)5 using both ab initio methods and UV-vis molar absorbance measurements. Our data indicate a strong dependence of both the position and intensity of UV absorbance features on oligonucleotide composition and stacking sequence. The partial densities of states for each oligonucleotide indicate that the valence band edge arises from a feature associated with the PO4(3-) complex anion, and the conduction band edge arises from anti-bonding states in DNA base pairs. The results show a strong correspondence between the ab initio and experimentally determined optical properties. These results highlight the benefit of full spectral analysis of DNA, as opposed to reductive methods that consider only the 260 nm absorbance (A260) or simple purity ratios, such as A260/A230 or A260/A280, and suggest that the slope of the absorption edge onset may provide a useful metric for the degree of base pair stacking in DNA. These insights may prove useful for applications in biology, bioelectronics, and mesoscale self-assembly.

Electronic structure, stacking energy, partial charge, and hydrogen bonding in four periodic B-DNA models.

We present a theoretical study of the electronic structure of four periodic B-DNA models labeled (AT)(10), (GC)(10), (AT)(5)(GC)(5), and (AT-GC)(5) where A denotes adenine, T denotes thymine, G denotes guanine, and C denotes cytosine. Each model has ten base pairs with Na counterions to neutralize the negative phosphate group in the backbone. The (AT)(5)(GC)(5) and (AT-GC)(5) models contain two and five AT-GC bilayers, respectively. When compared against the average of the two pure models, we estimate the AT-GC bilayer interaction energy to be 19.015 Kcal/mol, which is comparable to the hydrogen bonding energy between base pairs obtained from the literature. Our investigation shows that the stacking of base pairs plays a vital role in the electronic structure, relative stability, bonding, and distribution of partial charges in the DNA models. All four models show a highest occupied molecular orbital (HOMO) to lowest unoccupied molecular orbital (LUMO) gap ranging from 2.14 to 3.12 eV with HOMO states residing on the PO(4) + Na functional group and LUMO states originating from the bases. Our calculation implies that the electrical conductance of a DNA molecule should increase with increased base-pair mixing. Interatomic bonding effects in these models are investigated in detail by analyzing the distributions of the calculated bond order values for every pair of atoms in the four models including hydrogen bonding. The counterions significantly affect the gap width, the conductivity, and the distribution of partial charge on the DNA backbone. We also evaluate quantitatively the surface partial charge density on each functional group of the DNA models.