Blind prediction of HIV integrase binding from the SAMPL4 challenge

Here, we give an overview of the protein-ligand binding portion of the Statistical Assessment of Modeling of Proteins and Ligands 4 (SAMPL4) challenge, which focused on predicting binding of HIV integrase inhibitors in the catalytic core domain. The challenge encompassed three components—a small “virtual screening” challenge, a binding mode prediction component, and a small affinity prediction component. Here, we give summary results and statistics concerning the performance of all submissions at each of these challenges. Virtual screening was particularly challenging here in part because, in contrast to more typical virtual screening test sets, the inactive compounds were tested because they were thought to be likely binders, so only the very top predictions performed significantly better than random. Pose prediction was also quite challenging, in part because inhibitors in the set bind to three different sites, so even identifying the correct binding site was challenging. Still, the best methods managed low root mean squared deviation predictions in many cases. Here, we give an overview of results, highlight some features of methods which worked particularly well, and refer the interested reader to papers in this issue which describe specific submissions for additional details.     

An explanation of the unusual strength of the hydrogen bond in small water clusters

We seek to explain why the hydrogen bond possesses unusual strength in small water clusters that account for many of the complex behaviors of water. We have investigated and visualized the donation of covalent character from covalent (sigma) to hydrogen bonds by calculating the eigenvector coupling properties of quantum theory of atoms in molecules (QTAIM), stress tensor σ ( r ), and Ehrenfest Force F ( r ) on the F ( r ) molecular graph. The next-generation three-dimensional (3-D) bond-path framework sets are presented, and only the F ( r ) bond-path framework sets reproduce the earlier finding on the coupling between covalent (sigma) and hydrogen bonds that possess a degree of covalent character. Exploration of the bond-path between the covalent (sigma) and hydrogen bond's critical points provides an explanation for the previously obtained coupling results. The directional character of the covalent (sigma) and hydrogen bonds' 3-D bond-path framework sets for the F ( r ) explains differences found in the earlier results from QTAIM and the stress tensor σ ( r ).     

Guanidinoamidized linear polyethyleneimine for gene delivery

Guanidine was introduced to low molecular weight linear polyethyleneimine(LPEI) via amide groups, to explore the effect of both guanidine degree and pendant chain length on its transfection behavior. The resulting guanidinoamidized LPEIs(GLPEIs) could dramatically reduce LPEI's toxicity, enhance its DNA-packaging capability, cellular uptake and therefore transfection efficiency. These polyplexes were taken up very efficiently via caveolae-mediated endocytosis and their transfection efficiencies in ovarian cancer cells were significantly improved compared to native LPEI10 k polyplexes. Among these GLPEIs, LPEI-C3-G100 showed higher DNA affinity even than LPEI25 k and the highest transfection efficiency, probably due to the optimization of polymer chain flexibility. Of notice, LPEI-C3-G100 polyplexes could more effectively accumulate into cytoplasm than LPEI25 k, although the transfection efficiency of LPEI-C3-G100 polyplexes was not superior to that of LPEI25 k polyplexes, which would be probably attributed to the more efficient release of LPEI25 k polyplexes than LPEI-C3-G100 polyplexes in the cytoplasm.     

An Isserlis’ Theorem for Mixed Gaussian Variables: Application to the Auto-Bispectral Density

This work derives a version of Isserlis’ theorem for the specific case of four mixed-Gaussian random variables. The theorem is then used to derive an expression for the auto-bispectral density for quadratically nonlinear systems driven with mixed-Gaussian iid noise. C.C. Olson is a NRC Postdoctoral Research Associate.     

Thermochemistry of Binding of Lead(II) and Cadmium(II) by Saccharides in Aqueous Solution

Solution calorimetry was used to determine enthalpies and stability constants for binding of lead(II) or cadmium(II) by galacturonic acid and several monosaccharides in aqueous solution. New values for enthalpies of solution in water are reported for galacturonic acid and maltose monohydrate. The interaction of water solvent with the reactants is the largest factor in the binding process.     

Halophilic reactions of a stable silylene with chloro and bromocarbons

A number of disilanes have been synthesized from a stable silylene, 1 (N,N'-di-tert-butyl-1,3-diaza-2-silacyclopent-4-en-2-ylidene), and a variety of halocarbons. It is proposed that disilane formation is a result of an initial halophilic interaction between the silylene and halocarbon. Formation of disilanes from 1 and CCl4, 2a, CHCl3, 2b, CH2Cl2, 2c, benzyl chloride, 2d, and bromobenzene, 5, are described here. An X-ray crystal structure of 2b was determined.     

Bending of DNA by asymmetric charge neutralization: all-atom energy simulations

DNA dodecamers of the alternating d(CG).d(CG) sequence with six phosphate groups either charge-neutralized or substituted by neutral methylphosphonates across the major or minor groove have been subjected to energy minimization to determine the conformational effect of the asymmetric elimination of phosphate charge. We report bending angles, directions of bending, and detailed structural characteristics such as groove widths and local base-pair parameters. Our principal results are that charge neutralization on one face of the DNA induces significant bending toward the neutralized face, in agreement with theoretical predictions on a simplified model and experimental data on a similar base-pair sequence, and that the DNA conformation averaged over all stereospecific methylphosphonate substitutions is nearly the same as the conformation produced by charge neutralization of the phosphates. Individual isomers, however, cover a wide range of structures, with the magnitude and direction of overall bending sensitive to the precise stereochemical pattern of neutralization. Our simulation does not explicitly contain counterions, and the results therefore suggest that counterions can influence DNA structure by neutralizing the phosphate charge. These data provide new hints into the molecular mechanisms which underlie the deformations of DNA structure induced by the binding of positively charged proteins and other tightly associated cationic species.     

Conformation-dependent state selectivity in O-O cleavage of ONOONO: an "inorganic cope rearrangement" helps explain the observed negative activation energy in the oxidation of nitric oxide by dioxygen

ONOONO has been proposed as an intermediate in the oxidation of nitric oxide by dioxygen to yield nitrogen dioxide. The O-O bond breaking reactions of this unusual peroxide, and subsequent rearrangements, were evaluated using CBS-QB3 and B3LYP/6-311G hybrid density functional theory. The three stable conformers (cis,cis-, cis,trans-, and trans,trans-ONOONO, based on the O-N-O-O dihedral angles of either approximately 0 degrees or approximately 180 degrees ) are predicted to have very different O-O cleavage barriers: 2.4, 13.0, and 29.8 kcal/mol, respectively. These large differences arise because bond breaking leads to correlation of the nascent NO(2) fragments with either the ground (2)A(1) state or the excited (2)B(2) state of NO(2), depending on the starting ONOONO conformation. A cis-oriented NO(2) fragment correlates with the (2)A(1) state, whereas a trans-oriented NO(2) fragment correlates with the (2)B(2) state. Each NO(2) fragment that correlates with (2)A(1) lowers the O-O homolysis energy by approximately 15 kcal/mol, similar to the approximately 17-25 kcal/mol (2)A(1) --> (2)B(2) energy difference in NO(2). Hence, this provides an unusual example of conformation-dependent electronic state selectivity. The O-O bond homolysis of cis,cis-ONOONO is particularly interesting because it has a very low barrier and arises from the most stable ONOONO conformer, and also due to obvious similarities to the well-known [3,3]-sigmatropic shift of 1,5-hexadiene, i.e., the Cope rearrangement. As an additional proof of our state selectivity postulate, a comparison is also made to breakage of the O-O bond of cis,cis-formyl peroxide, where no significant stabilization of the transition state is available because the (2)A(1) and (2)B(2) states of formyloxy radical are near-degenerate in energy. In the case of trans,trans-ONOONO, the O-O bond breaking transition state is a concerted rearrangement yielding O(2)NNO(2), whereas for cis,cis- and cis,trans-ONOONO, the initially formed NO(2) radical pairs can undergo further rearrangement to yield ONONO(2). It is proposed that previous spectroscopic observations of certain N=O stretching frequencies in argon-matrix-isolated products from the reaction of NO with O(2) (or (18)O(2)) are likely from ONONO(2), not the OONO radical as reported.     

Colloidal dynamics on disordered substrates

Using Langevin simulations, we examine driven colloids interacting with quenched disorder. For weak substrates the colloids form an ordered state and depin elastically. For increasing substrate strength, we find a sharp crossover to inhomogeneous depinning and a substantial increase in the depinning force, analogous to the peak effect in superconductors. The velocity versus driving force curve shows criticality at depinning, with a change in scaling exponent occurring at the order to disorder crossover. Upon application of a sudden pulse of driving force, pronounced transients appear in the disordered regime which are due to the formation of long-lived colloidal flow channels.     

Observation of unusual surface ordering in a uniaxial Sm-A phase formed by a highly biaxial compound

We have studied one banana-shaped compound using null-transmission ellipsometry. By studying free-standing films of various thicknesses we confirm that this compound exhibits the Sm-A phase. This is the first banana-shaped compound with a relatively small bend angle (approximately 140 degrees) in which a uniaxial phase has been observed. At the lower temperature end of the Sm-A phase we observe unusual ordering at the surface of the film.