The Effect of Attractive Interactions and Macromolecular Crowding on Crystallins Association.

In living systems proteins are typically found in crowded environments where their effective interactions strongly depend on the surrounding medium. Yet, their association and dissociation needs to be robustly controlled in order to enable biological function. Uncontrolled protein aggregation often causes disease.

Analytic nuclear forces and molecular properties from full configuration interaction quantum Monte Carlo.

Unbiased stochastic sampling of the one- and two-body reduced density matrices is achieved in full configuration interaction quantum Monte Carlo with the introduction of a second, "replica" ensemble of walkers, whose population evolves in imaginary time independently from the first and which entails only modest additional computational overheads. The matrices obtained from this approach are shown to be representative of full configuration-interaction quality and hence provide a realistic opportunity to achieve high-quality results for a range of properties whose operators do not necessarily commute with the Hamiltonian. A density-matrix formulated quasi-variational energy estimator having been already proposed and investigated, the present work extends the scope of the theory to take in studies of analytic nuclear forces, molecular dipole moments, and polarisabilities, with extensive comparison to exact results where possible.

Accurate Ab initio calculation of ionization potentials of the first-row transition metals with the configuration-interaction quantum Monte Carlo technique.

Accurate ionization potentials of the first-row transition-metal atoms are obtained via the initiator full configuration quantum Monte Carlo technique, performing a stochastic integration of the electronic Schrödinger equation in exponentially large Hilbert spaces, with a mean absolute error of 0.13  kcal/mol (5 meV). This accuracy requires correlation of the 3p semicore electrons and in some cases the 3s manifold, along with extrapolation of the correlation energies to the complete-basis-set limit, and provides a new theoretical benchmark for the ionization potentials of these systems.

Symmetry Breaking and Broken Ergodicity in Full Configuration Interaction Quantum Monte Carlo.

The initiator full configuration interaction quantum Monte Carlo method (i-FCIQMC) is applied to the binding curve of N2 in Slater-determinant Hilbert spaces formed of both canonical restricted Hartree-Fock (RHF) and symmetry-broken unrestricted Hartree-Fock (UHF) orbitals. By explicit calculation, we demonstrate that the technique yields the same total energy for both types of orbital but that as the bond is stretched, FCI expansions expressed in unrestricted orbitals are substantially more compact than their restricted counterparts and more compact than those expressed in split-localized orbitals. These unrestricted Hilbert spaces, however, become nonergodic toward the dissociation limit, and the total wave function may be thought of as the sum of two weakly coupled, spin-impure, functions whose energies are nonetheless very close to the exact energy.

Nanoparticle organization in sandwiched polymer brushes.

The organization of nanoparticles inside grafted polymer layers is governed by the interplay of polymer-induced entropic interactions and the action of externally applied fields. Earlier work had shown that strong external forces can drive the formation of colloidal structures in polymer brushes. Here we show that external fields are not essential to obtain such colloidal patterns: we report Monte Carlo and molecular dynamics simulations that demonstrate that ordered structures can be achieved by compressing a "sandwich" of two grafted polymer layers, or by squeezing a coated nanotube, with nanoparticles in between.

Designing stimulus-sensitive colloidal walkers.

Colloidal particles with DNA "legs" that can bind reversibly to receptors on a surface can be made to 'walk' if there is a gradient in receptor concentration. We use a combination of theory and Monte Carlo simulations to explore how controllable parameters, e.g.

Conversion of aldoximes into nitriles and amides under mild conditions.

A series of Pd(en)X2 salts were used as catalysts for the conversion of aldoximes into nitriles and amides. Highlights of this protocol include the use of inexpensive polar solvents, including water, and moderate reaction temperatures. A high degree of selectivity in the reaction outcome was observed when using aliphatic vs.

A hybrid scanning mode for fast scanning ion conductance microscopy (SICM) imaging.

We have developed a new method of controlling the pipette for scanning ion conductance microscopy to obtain high-resolution images faster. The method keeps the pipette close to the surface during a single line scan but does not follow the exact surface topography, which is calculated by using the ion current. Using an FPGA platform we demonstrate this new method on model test samples and then on live cells.

Computational chemistry and cheminformatics: an essay on the future.

Computers have changed the way we do science. Surrounded by a sea of data and with phenomenal computing capacity, the methodology and approach to scientific problems is evolving into a partnership between experiment, theory and data analysis. Given the pace of change of the last twenty-five years, it seems folly to speculate on the future, but along with unpredictable leaps of progress there will be a continuous evolution of capability, which points to opportunities and improvements that will certainly appear as our discipline matures.

Targeting the c-Kit Promoter G-quadruplexes with 6-Substituted Indenoisoquinolines.

Herein, we demonstrate the design, synthesis, biophysical properties, and preliminary biological evaluation of 6-substituted indenoisoquinolines as a new class of G-quadruplex stabilizing small molecule ligands. We have synthesized 6-substituted indenoisoquinolines 1a-e in two steps from commercially available starting materials with excellent yields. The G-quadruplex stabilization potential of indenoisoquinolines 1a-e was evaluated by fluorescence resonance energy transfer-melting analysis, which showed that indenoisoquinolines show a high level of stabilization of various G-quadruplex DNA structures.

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules.

Biologically active molecules can be identified through the screening of small-molecule libraries. Deficiencies in current compound collections are evidenced by the continuing decline in drug-discovery successes. Typically, such collections are comprised of large numbers of structurally similar compounds.

RNA conformation in catalytically active human telomerase.

We have used single-molecule fluorescence microscopy to study the folded state of human telomerase RNA (hTR). Here we show that hTR adopts a new conformation on binding to human telomerase reverse transcriptase (hTERT) and reconstitution of an active ribonucleoprotein complex. Our data are consistent with the formation of an RNA pseudoknot in active human telomerase.

A small molecule that disrupts G-quadruplex DNA structure and enhances gene expression.

It has been hypothesized that the formation of G-quadruplex structures in the DNA of gene promoters may be functionally linked to transcription and consequently that small molecules that interact with such G-quadruplexes may modulate transcription. We previously reported that triarylpyridines are a class of small molecules that selectively interact with G-quadruplex DNA. Here we describe an unexpected property of one such ligand that was found to disrupt the structure of two different DNA G-quadruplex structures, each derived from sequence motifs in the promoter of the proto-oncogene c-kit.

Is synthesis the main hurdle for the generation of diversity in compound libraries for screening?

Background: 'Diversity' is often cited as a crucial consideration when generating compound collections for biological screening. However, what exactly does one mean by 'diversity' and why is it important?

Objective: How can diversity be incorporated into compound collections and what are the theoretical and technical challenges this poses? In this editorial, we comment on various factors involved in the creation of structurally, and most crucially, functionally diverse compound libraries.

Conclusions: In particular, we highlight the central role played by organic synthesis and discuss the value of diversity-driven synthetic approaches in the search for new biologically active molecules with potentially exciting and unusual biological properties.

Controlled-folding of a small molecule modulates DNA G-quadruplex recognition.

Differential recognition of diverse G-quadruplex structures can be achieved by controlling the folding of a small molecule.

Diarylethynyl amides that recognize the parallel conformation of genomic promoter DNA G-quadruplexes.

We report bis-phenylethynyl amide derivatives as a potent G-quadruplex binding small molecule scaffold. The amide derivatives were efficiently prepared in 3 steps by employing Sonogashira coupling, ester hydrolysis and a chemoselective amide coupling. Ligand-quadruplex recognition has been evaluated using a fluorescence resonance energy transfer (FRET) melting assay, surface plasmon resonance (SPR), circular dichroism (CD) and (1)H nuclear magnetic resonance (NMR) spectroscopy.

A novel small molecule that alters shelterin integrity and triggers a DNA-damage response at telomeres.

We describe a novel synthetic small molecule which shows an unprecedented stabilization of the human telomeric G-quadruplex with high selectivity relative to double-stranded DNA. We report that this compound can be used in vitro to inhibit telomerase activity and to uncap human POT1 (protection of telomeres 1) from the telomeric G-overhang. We also show that the small molecule G-quadruplex binder induces a partial alteration of shelterin through POT1 uncapping from telomeres in human HT1080 cancer cells and the presence of gammaH2AX foci colocalized at telomeres.

Selective recognition of a DNA G-quadruplex by an engineered antibody.

Particular guanine rich nucleic acid sequences can fold into stable secondary structures called G-quadruplexes. These structures have been identified in various regions of the genome that include the telomeres, gene promoters and UTR regions, raising the possibility that they may be associated with biological function(s). Computational analysis has predicted that intramolecular G-quadruplex forming sequences are prevalent in the human genome, thus raising the desire to differentially recognize genomic G-quadruplexes.

Triarylpyridines: a versatile small molecule scaffold for G-quadruplex recognition.

The triarylpyridines are potent G-quadruplex ligands that are highly discriminating against duplex DNA and show promising selectivity between intramolecular quadruplexes.

Modeling Aromatic Liquids: Toluene, Phenol, and Pyridine.

Aromatic groups are now acknowledged to play an important role in many systems of interest. However, existing molecular mechanics methods provide a poor representation of these groups. In a previous paper, we have shown that the molecular mechanics treatment of benzene can be improved by the incorporation of an explicit representation of the aromatic π electrons.

Oxazole-based peptide macrocycles: a new class of G-quadruplex binding ligands.

Herein we report on the synthesis and DNA binding properties of a new class of water soluble oxazole-based peptide macrocycles that bind selectively to quadruplex DNA, with no detectable binding to duplex DNA. We have recently identified one quadruplex in the proto-oncogene c-kit that is suspected to act as a regulatory element for the expression of the c-kit gene. Here we provide the first example of a ligand binding to and stabilizing the c-kit quadruplex.

Evidence that a novel thioesterase is responsible for polyketide chain release during biosynthesis of the polyether ionophore monensin.

Polyether ionophores, such as monensin A, are known to be biosynthesised, like many other antibiotic polyketides, on giant modular polyketide synthases (PKSs), but the intermediates and enzymes involved in the subsequent steps of oxidative cyclisation remain undefined. In particular there has been no agreement on the mechanism and timing of the final polyketide chain release. We now report evidence that MonCII from the monensin biosynthetic gene cluster in Streptomyces cinnamonensis, which was previously thought to be an epoxide hydrolase, is a novel thioesterase that belongs to the alpha/beta-hydrolase structural family and might catalyse this step.

The Structure of Liquid Benzene.

The interactions of aromatic groups have been identified as playing a crucial role in many systems of interest. Unfortunately, conventional atom-centered force fields provide only an approximate representation of these molecules owing to their failure to consider the quadrupole moment arising from the π electrons. In this paper the structure of liquid benzene, the prototypical aromatic system, is investigated using a novel approach to Monte Carlo simulation, parametrized against experimental thermodynamic data, which incorporates an explicit representation of the aromatic π electrons.

Distributed polarizabilities obtained using a constrained density-fitting algorithm.

A computationally efficient method for obtaining distributed polarizabilities of arbitrary rank using a constrained density-fitting algorithm is demonstrated on the hydrogen, carbon dioxide, formamide, and N-methylpropanamide molecules. A description of the molecular polarization in terms of local polarizabilities without charge-flow terms is obtained when the nonlocal components of the polarizability tensor are transformed away using the localization method of Le Sueur and Stone [Mol. Phys.