Design and optimization of targeted drug-like compounds is an important part of the early stage drug discovery process. In this paper, we describe the use of a novel technique for rapid design of lead-like compounds for the Dengue viral RNA-dependent-RNA polymerase (RdRp). Initially, a large (>billions) fragment-based chemical library is designed by mapping relevant pharmacophores to the target binding pocket. The de-novo synthesis of molecules from fragments is formulated as a quadratic unconstrained binary optimization problem that can be solved using the quantum-inspired Digital Annealer (DA), providing an opportunity to take advantage of this fledgling, groundbreaking technology. The DA constrains the search space of molecules with drug-like properties that match the binding pocket and then optimizes for synthetic feasibility and novelty, thus offering significant commercial advantages over existing techniques.

We have performed the first systematic density functional theory study of the coordination of three biomedically significant ligands, acetylcysteine, dihydrolipoic acid, and dopamine, to a small quantum dot (QD), Zn6S6. An exhaustive search for the global minima structures of the ligands and of the ligand-QD species identified several isomers of each compound close in energy to the global minimum structures. The isomeric variety is explained by the presence of several functional groups in the ligands and thus by numerous possibilities of their coordination to the QD. The global minimum structures of the three ligand-QD complexes were further studied with a larger basis set and implicit water effects. The three complexes were shown to be stable, with the anionic ligand species coordinated to the QD being generally more stable than the neutral compounds. The QD distortions because of the coordination with the anionic ligands were much more pronounced than those with the neutral ligands. Charge transfer from both the neutral and anionic ligands to the QD upon the ligand coordination was detected.

Actin bundles are key factors in the mechanical support and dynamic reorganization of the cytoskeleton. High concentrations of multivalent counterions promote bundle formation through electrostatic attraction between actin filaments that are negatively charged polyelectrolytes. In this study, we evaluate how physiologically relevant divalent cations affect the mechanical, dynamic, and structural properties of actin bundles. Using a combination of total internal reflection fluorescence microscopy, transmission electron microscopy, and dynamic light scattering, we demonstrate that divalent cations modulate bundle stiffness, length distribution, and lateral growth. Molecular dynamics simulations of an all-atom model of the actin bundle reveal specific actin residues coordinate cation-binding sites that promote the bundle formation. Our work suggests that specific cation interactions may play a fundamental role in the assembly, structure, and mechanical properties of actin bundles.

Self-assembling circuit elements, such as current splitters or combiners at the molecular scale, require the design of building blocks with three or more terminals. A promising material for such building blocks is DNA, wherein multiple strands can self-assemble into multi-ended junctions, and nucleobase stacks can transport charge over long distances. However, nucleobase stacking is often disrupted at junction points, hindering electric charge transport between the two terminals of the junction. Here, we show that a guanine-quadruplex (G4) motif can be used as a connector element for a multi-ended DNA junction. By attaching specific terminal groups to the motif, we demonstrate that charges can enter the structure from one terminal at one end of a three-way G4 motif, and can exit from one of two terminals at the other end with minimal carrier transport attenuation. Moreover, we study four-way G4 junction structures by performing theoretical calculations to assist in the design and optimization of these connectors.

Charge transport across novel DNA junctions has been studied for several decades. From early attempts to move charge across DNA double crossover junctions to recent studies on DNA three-way junctions and G4 motifs, it is becoming clear that efficient cross-junction charge migration requires strong base-to-base electronic coupling at the junction, facilitated by favorable pi-stacking. We review recent progress toward the goal of manipulating and controlling charge transport through DNA junctions.

Detection of point mutations and single nucleotide polymorphisms in DNA and RNA has a growing importance in biology, biotechnology, and medicine. For the application at hand, hybridization assays are often used. Traditionally, they differentiate point mutations only at elevated temperatures (>40 °C) and in narrow intervals (ΔT = 1-10 °C). The current study demonstrates that a specially designed multistranded DNA probe can differentiate point mutations in the range of 5-40 °C. This unprecedentedly broad ambient-temperature range is enabled by a controlled combination of (i) nonequilibrium hybridization conditions and (ii) a mismatch-induced increase of equilibration time in respect to that of a fully matched complex, which we dub "kinetic inversion".

DNA autoionization is a fundamental process wherein ultraviolet (UV)-photoexcited nucleobases dissipate energy by charge transfer to the environment without undergoing chemical damage. Here, single-wall carbon nanotubes (SWNT) are explored as a photoluminescent reporter for the study of the mechanism and rates of DNA autoionization. Two-color photoluminescence spectroscopy allows separate photoexcitation of the DNA and the SWNTs in the UV and visible range, respectively. A strong SWNT photoluminescence quenching is observed when the UV pump is resonant with the DNA absorption, consistent with charge transfer from the excited states of the DNA to the SWNT. Semiempirical calculations of the DNA-SWNT electronic structure, combined with a Green's function theory for charge transfer, show a 20 fs autoionization rate, dominated by hole transfer. Rate-equation analysis of the spectroscopy data confirms that the quenching rate is limited by thermalization of the free charge carriers transferred to the nanotube reservoir. This approach has great potential for monitoring DNA excitation, autoionization, and chemical damage, both in vivo and in vitro.

Significance Electron transport through DNA plays a central role in nucleic acid damage and repair, and it is usually modeled using a carrier tunneling mechanism (at short distances) and a hopping mechanism (at longer distances). We find that fluctuations into transient geometries that bring multiple bases into electronic degeneracy may support band-like transport during the resonance lifetimes over a distance of ≲15 Å, obviating the need to invoke electron tunneling at short distances. This line of research may help to reveal mechanisms of charge transport in multiheme proteins, bacterial nanowires, and synthetic nanowires, and may also assist in framing the mechanisms of coherent multipigment excitonic transport in light-harvesting proteins.

Charge transfer (CT) properties are compared between peptide nucleic acid structures with an aminoethylglycine backbone (aeg-PNA) and those with a γ-methylated backbone (γ-PNA). The common aeg-PNA is an achiral molecule with a flexible structure, whereas γ-PNA is a chiral molecule with a significantly more rigid structure than aeg-PNA. Electrochemical measurements show that the CT rate constant through an aeg-PNA bridging unit is twice the CT rate constant through a γ-PNA bridging unit. Theoretical calculations of PNA electronic properties, which are based on a molecular dynamics structural ensemble, reveal that the difference in the CT rate constant results from the difference in the extent of backbone fluctuations of aeg- and γ-PNA. In particular, fluctuations of the backbone affect the local electric field that broadens the energy levels of the PNA nucleobases. The greater flexibility of the aeg-PNA gives rise to more broadening, and a more frequent appearance of high-CT rate conformations than in γ-PNA.

We present evidence for a near-resonant mechanism of charge transfer in short peptide nucleic acid (PNA) duplexes obtained through electrochemical, STM break junction (STM-BJ), and computational studies. A seven base pair (7-bp) PNA duplex with the sequence (TA)(3)-(XY)-(TA)(3) was studied, in which XY is a complementary nucleobase pair. The experiments showed that the heterogeneous charge transfer rate constant (k(0)) and the single-molecule conductance (σ) correlate with the oxidation potential of the purine base in the XY base pair. The electrochemical measurements showed that the enhancement of k(0) is independent, within experimental error, of which of the two PNA strands contains the purine base of the XY base pair. 7-bp PNA duplexes with one or two GC base pairs had similar measured k(0) and conductance values. While a simple superexchange model, previously used to rationalize charge transfer in single stranded PNA (Paul et al. J. Am. Chem. Soc. 2009, 131, 6498-6507), describes some of the experimental observations, the model does not explain the absence of an enhancement in the experimental k(0) and σ upon increasing the G content in the duplexes from one to two. Moreover, the superexchange model is not consistent with other studies (Paul et al. J. Phys. Chem. B 2010, 114, 14140), that showed a hopping charge transport mechanism is likely important for PNA duplexes longer than seven base pairs. A quantitative computational analysis shows that a near-resonant charge transfer regime, wherein a mix of superexchange and hopping mechanisms are expected to coexist, can rationalize all of the experimental results.

The electronic structure of self-assembled monolayers (SAMs) of peptide nucleic acid (PNA) formed on Au substrates was investigated. Cys-appended PNA 7-mers of thymine (Cys-T7) were incubated on Au substrates in a nitrogen glovebox attached to a photoemission spectrometer. Ultraviolet and X-ray photoemission spectroscopy (UPS and XPS) measurements on the resulting SAMs revealed the hole injection barrier at the interface and the interface dipole. Electronic structure calculations based on molecular dynamics sampling of the PNA structure yielded the HOMO-LUMO gap and the electronic density of states for PNA. Combined with the UPS data, the theoretical calculation enabled estimation Of the Au charge injection barriers at the interface as well as the assignment of individual UP spectral features to specific molecular orbitals. Interestingly, the dipole moment of the PNA backbone is predicted to polarize PNA MOs, shifting the preferred HOMO localization toward the C-terminus of PNA. Control measurements on Cys-appended, abasic pNA backbone 7-mers (Cys-Bckb7) allowed the identification of the emissions related to the PNA backbone in the UP spectra. The orbital line-up at the interface between the Au substrate and the Cys-PNA indicates a significant interface dipole resulting in the alignment of the Au Fermi level near the center of the PNA HOMO-LUMO gap. This alignment causes large charge injection barriers for both holes and electrons, and thus impedes charge transfer from Au into the Cys-PNA SAM.

The forced extension of a DNA segment is studied in a series of steered molecular dynamics simulations, employing a broad range of pulling forces. Throughout the entire force range, the formation of a zipper-like (zip-) DNA structure is observed. In that structure, first predicted by Lohikoski et al., the bases of the DNA strands interdigitate with each other and form a single-base aromatic stack. Similar motifs, albeit only a few base pairs in extent, have been observed in experimental crystal structures. Analysis of the dynamics of structural changes in pulled DNA shows that S-form DNA, thought to be adopted by DNA under applied force, serves as an intermediate between B-DNA and zip-DNA. Therefore, the phase transition plateau observed in force-extension curves of DNA is suggested to reflect the B-DNA to zip-DNA structural transition. Electronic structure analysis of purine bases in zip-DNA indicates a several-fold to order of magnitude increase in the π-π electronic coupling among nearest-neighbor nucleobases, compared to B-DNA. We further observe that zip-DNA does not require base pair complementarity between DNA strands, and we predict that the increased electronic coupling in zip-DNA will result in a much higher rate of charge transfer through an all-purine zip-DNA compared to B-DNA of equal length.

Theoretical studies of charge transport in deoxyribonucleic acid (DNA) and peptide nucleic acid (PNA) indicate that structure and dynamics modulate the charge transfer rates, and that different members of a structural ensemble support different charge transport mechanisms. Here, we review the influences of nucleobase geometry, electronic structure, solvent environment, and thermal conformational fluctuations on the charge transfer mechanism. We describe an emerging framework for understanding the diversity of charge transport mechanisms seen in nucleic acids.

It has been shown in many experimental studies that one of the major charge-transfer mechanisms in nucleic acids is that by positive charge carriers (holes), residing predominantly on G bases. Theoretical charge-transfer calculations often use Koopmans' theorem to approximate the relaxed doublet cation hole energies from simulations of the neutral ground state (GS). An assumption in these calculations is that the geometry and interactions of the doublet cation (DC) hole with the solvent is the same as that for the neutral GS. Here, we simulate the DC hole on solvated G and A nucleobases using combined quantum mechanics/molecular mechanics (QM/MM) methods and compare the geometries and electronic structure of the charged bases to those of the neutral bases. We also study the effects of the solvent environment on the nucleobase electronic structure and estimate the size of the smallest solvent shell that needs to be included in order to achieve convergence of the nucleobase energy levels. We find that Koopmans' theorem based methods provide a satisfactory description of the nucleobase energy levels, with the largest deviation (similar to 0.1 eV) for charged bases in explicit water. We also find that the size of the solvent shell is crucial for describing the nucleobase electronic structure. When the solvent is properly accounted for, we find that the average energy separation between the hole energy levels on isolated G and A is similar to 0.2 eV, and the hole energy levels fluctuate by similar to 0.3 eV. These findings suggest important corrections to earlier theoretical studies that overestimated the hole energy separation among nucleobases and underestimated or neglected the base energy distribution due to thermal fluctuations of the nucleobases and their environment. Our results further suggest that hopping charge transport plays an important role even at short distances.