Docking validation resources: protein family and ligand flexibility experiments

A database consisting of 780 ligand-receptor complexes, termed SB2010, has been derived from the Protein Databank to evaluate the accuracy of docking protocols for regenerating bound ligand conformations. The goal is to provide easily accessible community resources for development of improved procedures to aid virtual screening for ligands with a wide range of flexibilities. Three core experiments using the program DOCK, which employ rigid (RGD), fixed anchor (FAD), and flexible (FLX) protocols, were used to gauge performance by several different metrics: (1) global results, (2) ligand flexibility, (3) protein family, and (4) cross-docking. Global spectrum plots of successes and failures vs rmsd reveal well-defined inflection regions, which suggest the commonly used 2 ? criteria is a reasonable choice for defining success. Across all 780 systems, success tracks with the relative difficulty of the calculations: RGD (82.3%) > FAD (78.1%) > FLX (63.8%). In general, failures due to scoring strongly outweigh those due to sampling. Subsets of SB2010 grouped by ligand flexibility (7-or-less, 8-to-15, and 15-plus rotatable bonds) reveal that success degrades linearly for FAD and FLX protocols, in contrast to RGD, which remains constant. Despite the challenges associated with FLX anchor orientation and on-the-fly flexible growth, success rates for the 7-or-less (74.5%) and, in particular, the 8-to-15 (55.2%) subset are encouraging. Poorer results for the very flexible 15-plus set (39.3%) indicate substantial room for improvement. Family-based success appears largely independent of ligand flexibility, suggesting a strong dependence on the binding site environment. For example, zinc-containing proteins are generally problematic, despite moderately flexible ligands. Finally, representative cross-docking examples, for carbonic anhydrase, thermolysin, and neuraminidase families, show the utility of family-based analysis for rapid identification of particularly good or bad docking trends, and the type of failures involved (scoring/sampling), which will likely be of interest to researchers making specific receptor choices for virtual screening. SB2010 is available for download at http://rizzolab.org .     

Feasibility of Using Bimetallic Plasmonic Nanostructures to Enhance the Intrinsic Emission of Biomolecules

Detection of the intrinsic fluorescence from proteins is important in bio-assays because it can potentially eliminate the labeling of external fluorophores to proteins. This is advantageous because using external fluorescent labels to tag biomolecules requires chemical modification and additional incubation and washing steps which can potentially perturb the native functionality of the biomolecules. Hence the external labeling steps add expense and complexity to bio-assays. In this paper, we investigate for the first time the feasibility of using bimetallic nanostructures made of silver (Ag) and aluminum (Al) to implement the metal enhanced fluorescence (MEF) phenomenon for enhancing the intrinsic emission of biomolecules in the ultra-violet (UV) spectral region. Fluorescence intensities and lifetimes of a tryptophan analogue N-acetyl-L-tryptophanamide (NATA) and a tyrosine analogue N-acetyl-L-tyrosinamide (NATA-tyr) were measured. Increase in fluorescence intensities of upto 10-fold and concurrent decrease in lifetimes for the amino acids were recorded in the presence of the bimetallic nanostructures when compared to quartz controls. We performed a model protein assay involving biotinylated bovine serum albumin (bt-BSA) and streptavidin on the bimetallic nanostructured substrate to investigate the distance dependent effects on the extent of MEF from the bimetallic nanostructures and found a maximum enhancement of over 15-fold for two layers of bt-BSA and streptavidin. We also used finite difference time domain (FDTD) calculations to explore how bimetallic nanostructures interact with plane waves and excited state fluorophores in the UV region and demonstrate that the bimetallic substrates are an effective platform for enhancing the intrinsic emission of proteins and other biomolecules.     

A FrameWork for the Error Analysis of Discontinuous Finite Element Methods for Elliptic Optimal Control Problems and Applications to C 0 IP Methods

In this article, an abstract framework for the error analysis of discontinuous Galerkin methods for control constrained optimal control problems is developed. The analysis establishes the best approximation result from a priori analysis point of view and delivers a reliable and efficient a posteriori error estimator. The results are applicable to a variety of problems just under the minimal regularity possessed by the well-posedness of the problem. Subsequently, the applications of C ⁰ interior penalty methods for a boundary control problem as well as a distributed control problem governed by the biharmonic equation subject to simply supported boundary conditions are discussed through the abstract analysis. Numerical experiments illustrate the theoretical findings.     

Effect of chain length and donor–acceptor substitution on the electrical responsive properties of conjugated biphenyls: a DFT-based computational study

The effect of donor–acceptor (D-A) substituent and chain length on the electrical polarisabilities and first hyper polarisability of cis and trans biphenyl oligomeric compounds have been investigated using density functional theory-based hybrid functional CAM-B3LYP with 6-311G (2d,2p) basis set. Our extensive computational study reveals that both average polarisability and first hyper polarisability of the studied compounds increase with the increasing ethylene spacer chain length. Again the substitution of donor (NMe₂) and acceptor (C≡N) at the para position of the phenyl rings to each oligomer shows order of magnitude increase of both α_av and β_av value compared to the unsubstituted one. This increased α_av and β_av values have been explained due to increasing charge transfer contribution resulting from decreasing optical energy gap (ΔE?=?S₁???S₀) upon D-A substitution. It is also observed that the charge transfer contribution to first hyperpolarisability (β_CT) is more than the polarisability (α_CT) for the studied molecules. The electronic spatial extent (<R²>) which is a measure of electron density volume around the molecule is found to play a major role along with the intramolecular charge transfer character to explain the non-linear variation of first hyperpolarisability (β_av) as a function of ethylene spacer chain length (n) and D-A substitution.     

Benford analysis of quantum critical phenomena: First digit provides high finite-size scaling exponent while first two and further are not much better

Benford's law is an empirical edict stating that the lower digits appear more often than higher ones as the first few significant digits in statistics of natural phenomena and mathematical tables. A marked proportion of such analyses is restricted to the first significant digit. We employ violation of Benford's law, up to the first four significant digits, for investigating magnetization and correlation data of paradigmatic quantum many-body systems to detect cooperative phenomena, focusing on the finite-size scaling exponents thereof. We find that for the transverse field quantum XY model, behavior of the very first significant digit of an observable, at an arbitrary point of the parameter space, is enough to capture the quantum phase transition in the model with a relatively high scaling exponent. A higher number of significant digits do not provide an appreciable further advantage, in particular, in terms of an increase in scaling exponents. Since the first significant digit of a physical quantity is relatively simple to obtain in experiments, the results have potential implications for laboratory observations in noisy environments.     

A molecular simulation based assessment of binding of metal ions on micelles

An assessment of the ability of a micellar surface to bind different metal ions using molecular simulation is presented in this study. Sodium dodecyl sulfate (SDS) is considered as the anionic surfactant. Various relevant characteristics of SDS-metal ion systems are estimated to quantify preferential binding of metal ions. These are electrostatic energy, total potential energy of the system, radial distribution function, and entropy and free energy change of the system. By examining these parameters, the relative extents of binding of different metal ions to the micellar surface are assessed.     

Evaluation of DOCK 6 as a pose generation and database enrichment tool

In conjunction with the recent American Chemical Society symposium titled "Docking and Scoring: A Review of Docking Programs" the performance of the DOCK6 program was evaluated through (1) pose reproduction and (2) database enrichment calculations on a common set of organizer-specified systems and datasets (ASTEX, DUD, WOMBAT). Representative baseline grid score results averaged over five docking runs yield a relatively high pose identification success rate of 72.5?% (symmetry corrected rmsd) and sampling rate of 91.9?% for the multi site ASTEX set (N?=?147) using organizer-supplied structures. Numerous additional docking experiments showed that ligand starting conditions, symmetry, multiple binding sites, clustering, and receptor preparation protocols all affect success. Encouragingly, in some cases, use of more sophisticated scoring and sampling methods yielded results which were comparable (Amber score ligand movable protocol) or exceeded (LMOD score) analogous baseline grid-score results. The analysis highlights the potential benefit and challenges associated with including receptor flexibility and indicates that different scoring functions have system dependent strengths and weaknesses. Enrichment studies with the DUD database prepared using the SB2010 preparation protocol and native ligand pairings yielded individual area under the curve (AUC) values derived from receiver operating characteristic curve analysis ranging from 0.29 (bad enrichment) to 0.96 (good enrichment) with an average value of 0.60 (27/38 have AUC?≥?0.5). Strong early enrichment was also observed in the critically important 1.0-2.0?% region. Somewhat surprisingly, an alternative receptor preparation protocol yielded comparable results. As expected, semi-random pairings yielded poorer enrichments, in particular, for unrelated receptors. Overall, the breadth and number of experiments performed provide a useful snapshot of current capabilities of DOCK6 as well as starting points to guide future development efforts to further improve sampling and scoring.     

Effect of change of water structure on the phase transition of liposomes of dipalmitoyl phosphatidylcholine

The role of water structure around model membrane systems (e.g., liposomes) on phase transition of the lipid dipalmitoyl phosphatidylcholine was investigated. Water structure was altered by changing pH and by addition of solutes which are known breakers and makers of water structure. The structure makers broadened the zone of transition and changed the overall phase transition profile, while the main effect of structure breakers was to cause a shift in the transition temperature. The observed variation of Chapman transition temperature and broadening of zone of transition with varying pH is discussed in terms of altered water structure around the membrane–aqueous interface. Binding studies with the dye 1-anilino-8-napthalene sulfonate showed that structure makers or breakers did not bind to the liposome surface directly. Thus the structure makers and breakers act on the membranes perhaps by altering the water structure differentially. Possible associated mechanisms of action are discussed.