An all-atom model of the human cardiac sodium channel in a lipid bilayer.

Voltage-gated sodium channels (Na) are complex macromolecular proteins that are responsible for the initial upstroke of an action potential in excitable cells. Appropriate function is necessary for many physiological processes such as heartbeat, voluntary muscle contraction, nerve conduction, and neurological function. Dysfunction can have life-threatening consequences.

Computational modeling to understand the interaction of TMPyP4 with a G-quadruplex.

The potential of small molecules to bind to G-quadruplex-forming sequences in oncogene promoter regions, thereby regulating their structural equilibrium, has been explored as a promising strategy for cancer chemotherapy. The model drug 5,10,15,20-tetrakis-(N-methyl-4-pyridyl)porphine (TMPyP4) has been shown to have an affinity toward G-quadruplex DNA. However, the precise sites and modes of TMPyP4 binding to G-quadruplex DNA remain a subject of debate.

Extending the Perturbative Triples Correction in Coupled-Cluster Theory to Account for Inactive Orbitals.

Coupled-cluster singles and doubles calculations with perturbative triples [CCSD(T)] offer high accuracy with significant cost. The standard way to reduce the cost of a CCSD(T) calculation is by excluding molecular orbitals from the correlated calculation. While this speeds up the calculation, it also throws away the contribution from the inactive orbitals to the correlation energy.

Protein Binding Leads to Reduced Stability and Solvated Disorder in the Polystyrene Nanoparticle Corona.

Understanding the conformation of proteins in the nanoparticle corona has important implications in how organisms respond to nanoparticle-based drugs. These proteins coat the nanoparticle surface, and their properties will influence the nanoparticle's interaction with cell targets and the immune system. While some coronas are thought to be disordered, two key unanswered questions are the degree of disorder and solvent accessibility.

Computed interactions of berenil with restricted foldamers of c-MYC DNA G-quadruplexes.

G-quadruplexes (G4s) are secondary four-stranded DNA helical structures made up of guanine-rich nucleic acids that can assemble in the promoter regions of multiple genes under the appropriate conditions. Stabilization of G4 structures by small molecules can regulate transcription in non-telomeric regions, including in proto-oncogenes and promoter regions, contributing to anti-proliferative and anti-tumor activities. Because G4s are detectable in cancer cells but not in normal cells, they make excellent drug discovery targets.

Thienylpiperidine Donor NIR Xanthene-Based Dye for Photoacoustic Imaging.

Few xanthene-based near-infrared (NIR) photoacoustic (PA) dyes with absorbance >800 nm exist. As accessibility to these dyes requires long and tedious synthetic steps, we designed a NIR dye () with thienylpiperidine donors and a xanthene acceptor that is accessible in 3-4 synthetic steps. The dye boasts a strong PA signal at 880 nm with good biological compatibility and photostability, yields multiplexed imaging with an aza-BODIPY reference dye, and is detected at a depth of 4 cm.

Cyclooctadiene Rh(I) Bis- and Tris(pyrazolyl)aluminate Complexes and Their Catalytic Activity on the Polymerization of Phenylacetylene.

In this work, we report the transfer of alkyl bis- and tris(pyrazolyl)aluminates metalloligands to an electron-rich organotransition metal center. The 16-electron heterobimetallic complexes of rhodium [Rh(COD){Al(Phpz)Me}] () and [Rh(COD){Al(Phpz)Me}] () were obtained by metathesis reaction of the sodium bis- () and tris(pyrazolyl)aluminate () with [RhCl(COD)]. For , H and C NMR in solution along with DFT calculations are consistent with a κ-coordination mode of the bis(pyrazolyl)aluminate to a square-planar Rh(I) center.

New Design Strategy Toward NIR I Xanthene-Based Dyes.

An effective design strategy with an efficient synthetic route to xanthene-based far-red to near-infrared dyes is reported. The dyes were prepared by the Suzuki cross-coupling of the electron-poor fluorescein ditriflate with the electron-rich boronic acid/ester-functionalized pyrrole () and indole () moieties. Upon treatment with trifluoroacetic acid, the closed nonfluorescent forms of the dyes ( and ) ring-opened to their fluorescent forms ( and ).

Dispersion-Corrected Modified Embedded-Atom Method Bond Order Interatomic Potential for Sulfur.

An interatomic potential for sulfur has been developed using the bond order addition to the modified embedded-atom method (MEAM-BO). In order to correctly model the interaction between molecules, dispersion forces have been included via the DFT-D3 modification. It is demonstrated that this semiempirical classical potential correctly reproduces the behavior of the S dimer, various cyclic sulfur rings, the molecular solids α-, β-, and γ-sulfur, and a number of theoretical, high symmetry sulfur structures.

Molecular dynamics simulations showing 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) membrane mechanoporation damage under different strain paths.

Continuum finite element material models used for traumatic brain injury lack local injury parameters necessitating nanoscale mechanical injury mechanisms be incorporated. One such mechanism is membrane mechanoporation, which can occur during physical insults and can be devastating to cells, depending on the level of disruption. The current study investigates the strain state dependence of phospholipid bilayer mechanoporation and failure.

Interatomic Potential for Hydrocarbons on the Basis of the Modified Embedded-Atom Method with Bond Order (MEAM-BO).

In this paper, we develop a new modified embedded atom method (MEAM) potential that includes the bond order (MEAM-BO) to describe the energetics of unsaturated hydrocarbons (double and triple carbon bonds) and also develop improved parameters for saturated hydrocarbons from those of our previous work. Such quantities like bond lengths, bond angles, and atomization energies at 0 K, dimer molecule interactions, rotational barriers, and the pressure-volume-temperature relationships of dense systems of small molecules give a comparable or more accurate property relative to experimental and first-principles data than the classical reactive force fields REBO and ReaxFF. Our extension of the MEAM potential for unsaturated hydrocarbons (MEAM-BO) is a step toward developing more reliable and accurate polymer simulations with their associated structure-property relationships, such as reactive multicomponent (organic/metal) systems, polymer-metal interfaces, and nanocomposites.

Novel nucleophiles enhance the human serum paraoxonase 1 (PON1)-mediated detoxication of organophosphates.

Paraoxonase 1 (PON1) is a calcium-dependent hydrolase associated with serum high-density lipoprotein particles. PON1 hydrolyzes some organophosphates (OPs), including some nerve agents, through nucleophilic attack of hydroxide ion (from water) in the active site. Most OPs are hydrolyzed inefficiently.

Structures and Stabilities of the Metal Doped Gold Nano-Clusters: M@Au (M = W, Mo, Ru, Co).

The structures and stabilities of a series of endohedral gold clusters containing ten gold atoms M@Au (M = W, Mo, Ru, Co) have been determined using density functional theory. The gradient-corrected functional BP86, the Tao-Perdew-Staroverov-Scuseria TPSS meta-GGA functional, and the hybrid density functionals B3LYP and PBE1PBE were employed to calculate the structures, binding energies, adiabatic ionization potentials, and adiabatic electron affinities for these clusters. The LanL2DZ effective core potentials and the corresponding valence basis sets were employed.

Calculations of relative intensities of fragment ions in the MSMS spectra of a doubly charged penta-peptide.

Background: Currently, the tandem mass spectrometry (MSMS) of peptides is a dominant technique used to identify peptides and consequently proteins. The peptide fragmentation inside the mass analyzer typically offers a spectrum containing several different groups of ions. The mass to charge (m/z) values of these ions can be exactly calculated following simple rules based on the possible peptide fragmentation reactions.

Global and local molecular dynamics of a bacterial carboxylesterase provide insight into its catalytic mechanism.

Carboxylesterases (CEs) are ubiquitous enzymes responsible for the detoxification of xenobiotics. In humans, substrates for these enzymes are far-ranging, and include the street drug heroin and the anticancer agent irinotecan. Hence, their ability to bind and metabolize substrates is of broad interest to biomedical science.

Transformation of Triclosan by Fe(III)-saturated montmorillonite.

Abiotic transformation of triclosan (TCS) was investigated by incubating TCS with Fe(III)- and Na-montmorillonite at 40% relative humidity and room temperature for up to 100 days. The TCS transformation products were characterized using LC/MS, GC/MS, and computational modeling and quantified using HPLC/UV and GC/MS. Within 1-5 days, depending on the initial TCS concentrations, about 55% of the TCS was rapidly transformed in the presence of Fe(III)-montmorillonite, producing 2,4-dichlorophenol, 3-chlorophenol, 2,4-dichlorophenol dimer, chlorophenoxy phenols, and TCS dimers and trimers.

Evaluation of the 'side door' in carboxylesterase-mediated catalysis and inhibition.

Abstract Structures of mammalian carboxylesterases (CEs) reveal the presence of a 'side door' that is proposed to act as an alternative pore for the trafficking of substrates and products. p-Nitrobenzyl esterase (pnb CE) from Bacillus subtilis exhibits close structural homology and a similar side-door domain as mammalian CEs. We investigated the role of a specific 'gate' residue at the side door (i.

Second-order correction to perfect pairing: an inexpensive electronic structure method for the treatment of strong electron-electron correlations.

We have formulated a second-order perturbative correction for perfect-pairing wave functions [PP2] based on similarity-transformed perturbation techniques in coupled cluster theory. The perfect-pairing approximation is used to obtain a simple reference wave function which can qualitatively describe bond breaking, diradicals, and other highly correlated systems, and the perturbative correction accounts for the dynamical correlation. An efficient implementation of this correction using the resolution of the identity approximation enables PP2 to be computed at a cost only a few times larger than that of canonical MP2 for systems with hundreds of active electrons and tens of heavy atoms.

Excitation spectra of dibenzoborole containing pi-electron systems: controlling the electronic spectra by changing the p(pi)-pi* conjugation.

We report time-dependent density functional theory calculations of the vertical excitation energies for the singlet states of three-coordinate 5H-dibenzoborole (DBB) derivatives and four-coordinate 5-fluoro-5H-dibenzoborole ion (FDBB) derivatives. These molecules show remarkable hypsochromic (blue) shifts in their fluorescence spectra and bathochromic (red) shifts in their absorption spectra when the bridging boron atoms change their coordination number from three to four. We constructed a series of derivatives of DBB and FDBB and studied how the energies of the electronic excitations change.

Charge-transfer mechanism for electrophilic aromatic nitration and nitrosation via the convergence of (ab initio) molecular-orbital and Marcus-Hush theories with experiments.

The highly disparate rates of aromatic nitrosation and nitration, despite the very similar (electrophilic) properties of the active species: NO(+) and NO(2)(+) in Chart 1, are quantitatively reconciled. First, the thorough mappings of the potential-energy surfaces by high level (ab initio) molecular-orbital methodologies involving extensive coupled-cluster CCSD(T)/6-31G optimizations establish the intervention of two reactive intermediates in nitration (Figure 8) but only one in nitrosation (Figure 7). Second, the same distinctive topologies involving double and single potential-energy minima (Figures 6 and 5) also emerge from the semiquantitative application of the Marcus-Hush theory to the transient spectral data.