Protein structure validation and refinement using amide proton chemical shifts derived from quantum mechanics

We present the ProCS method for the rapid and accurate prediction of protein backbone amide proton chemical shifts - sensitive probes of the geometry of key hydrogen bonds that determine protein structure. ProCS is parameterized against quantum mechanical (QM) calculations and reproduces high level QM results obtained for a small protein with an RMSD of 0.25 ppm (r = 0.94). ProCS is interfaced with the PHAISTOS protein simulation program and is used to infer statistical protein ensembles that reflect experimentally measured amide proton chemical shift values. Such chemical shift-based structural refinements, starting from high-resolution X-ray structures of Protein G, ubiquitin, and SMN Tudor Domain, result in average chemical shifts, hydrogen bond geometries, and trans-hydrogen bond (h3JNC') spin-spin coupling constants that are in excellent agreement with experiment. We show that the structural sensitivity of the QM-based amide proton chemical shift predictions is needed to refine protein structures to this agreement. The ProCS method thus offers a powerful new tool for refining the structures of hydrogen bonding networks to high accuracy with many potential applications such as protein flexibility in ligand binding.Comment: PLOS ONE accepted, Nov 201

Robust information from phylogenetic trees?

Traditional information criteria approaches can lead to misleading model choice in comparative phylogenetics. I present both these weaknesses and a more robust comparison by likelihood ratio. I then discuss a new class of models to capture the transition process between evolutionary regimes

The Olympic medals ranks, lexicographic ordering and numerical infinities

Several ways used to rank countries with respect to medals won during Olympic Games are discussed. In particular, it is shown that the unofficial rank used by the Olympic Committee is the only rank that does not allow one to use a numerical counter for ranking – this rank uses the lexicographic ordering to rank countries: one gold medal is more precious than any number of silver medals and one silver medal is more precious than any number of bronze medals. How can we quantify what do these words, more precious, mean? Can we introduce a counter that for any possible number of medals would allow us to compute a numerical rank of a country using the number of gold, silver, and bronze medals in such a way that the higher resulting number would put the country in the higher position in the rank? Here we show that it is impossible to solve this problem using the positional numeral system with any finite base. Then we demonstrate that this problem can be easily solved by applying numerical computations with recently developed actual infinite numbers. These computations can be done on a new kind of a computer – the recently patented Infinity Computer. Its working software prototype is described briefly and examples of computations are given. It is shown that the new way of counting can be used in all situations where the lexicographic ordering is required

The Study on the Evaluation of the Visual Work Using the Logistic Curve

Display equipment has been used as communication media in the factory, office, and home. In order to communicate effectively, it is necessary to clarify the characteristics of eye movement in the case of looking at the display. The development of Eye Camera enables us to measure eye movement during work, so that we can collect the many data of eye movement during work. In this study, we proposed a method to evaluate the visual work using the distribution of visual points in X and Y axis. The cumulative distribution is approximated by the logistic curve which shows the symmetry and kurtosis by the parameter. The proposed method was applied to the three typical display models, that is, the digital meter model, reading model, and game model. In the digital meter model, the visual points were distributed symmetrically along the meters, and the symmetry and kurtosis of the distribution varied by the arranged direction of the meter. In the reading model, the visual points were distributed nearly symmetrically and uniformly in each axis and they were moved around the character and line from the period of spectrum analysis. In the game model, the visual points moved according to the target and were distributed symmetrically in the Y axis. And whether the target moved vertically or horizontally, the kurtosis of the distribution became equal in each axis

Blockade of Neuronal α7-nAChR by α-Conotoxin ImI Explained by Computational Scanning and Energy Calculations

α-Conotoxins potently inhibit isoforms of nicotinic acetylcholine receptors (nAChRs), which are essential for neuronal and neuromuscular transmission. They are also used as neurochemical tools to study nAChR physiology and are being evaluated as drug leads to treat various neuronal disorders. A number of experimental studies have been performed to investigate the structure-activity relationships of conotoxin/nAChR complexes. However, the structural determinants of their binding interactions are still ambiguous in the absence of experimental structures of conotoxin-receptor complexes. In this study, the binding modes of α-conotoxin ImI to the α7-nAChR, currently the best-studied system experimentally, were investigated using comparative modeling and molecular dynamics simulations. The structures of more than 30 single point mutants of either the conotoxin or the receptor were modeled and analyzed. The models were used to explain qualitatively the change of affinities measured experimentally, including some nAChR positions located outside the binding site. Mutational energies were calculated using different methods that combine a conformational refinement procedure (minimization with a distance dependent dielectric constant or explicit water, or molecular dynamics using five restraint strategies) and a binding energy function (MM-GB/SA or MM-PB/SA). The protocol using explicit water energy minimization and MM-GB/SA gave the best correlations with experimental binding affinities, with an R2 value of 0.74. The van der Waals and non-polar desolvation components were found to be the main driving force for binding of the conotoxin to the nAChR. The electrostatic component was responsible for the selectivity of the various ImI mutants. Overall, this study provides novel insights into the binding mechanism of α-conotoxins to nAChRs and the methodological developments reported here open avenues for computational scanning studies of a rapidly expanding range of wild-type and chemically modified α-conotoxins