Flexibility and binding affinity in protein–ligand,protein–protein and multi-component protein interactions: limitations of current computational approaches

The recognition process between a protein and a partner represents a significant theoretical challenge. In silico structure-based drug design carried out with nothing more than the three-dimensional structure of the protein has led to the introduction of many compounds into clinical trials and numerous drug approvals. Central to guiding the discovery process is to recognize active among non-active compounds. While large-scale computer simulations of compounds taken from a library (virtual screening) or designed de novo are highly desirable in the post-genomic area, many technical problems remain to be adequately addressed. This article presents an overview and discusses the limits of current computational methods for predicting the correct binding pose and accurate binding affinity. It also presents the performances of the most popular algorithms for exploring binary and multi-body protein interactions.     

Active radiative liquid lithium divertor concept

Developing a reactor compatible divertor has been identified as a particularly challenging technology problem for magnetic confinement fusion. Application of lithium (Li) in NSTX resulted in improved H-mode confinement, H-mode power threshold reduction, and reduction in the divertor peak heat flux while maintaining essentially Li-free core plasma operation even during H-modes. These promising Li results in NSTX and related modeling calculations motivated the radiative liquid lithium divertor (RLLD) concept [1]. In the RLLD, Li is evaporated from the liquid lithium (LL) coated divertor strike point surface due to the intense heat flux. The evaporated Li is readily ionized by the plasma due to its low ionization energy, and the poor Li particle confinement near the divertor plate enables ionized Li ions to radiate strongly, resulting in a significant reduction in the divertor heat flux. This radiative process has the desired effect of spreading the localized divertor heat load to the rest of the divertor chamber wall surfaces, facilitating divertor heat removal. The modeling results indicated that the Li radiation can be quite strong, so that only a small amount of Li (∼a few mol/s) is needed to significantly reduce the divertor peak heat flux for typical reactor parameters. In this paper, we examine an active version of the RLLD, which we term ARLLD, where LL is injected in the upstream region of divertor. We find that the ARLLD has similar effectiveness in reducing the divertor heat flux as the RLLD, again requiring only a few mol/s of LL to significantly reduce the divertor peak heat flux for a reactor. An advantage of the ARLLD is that one can inject LL proactively even in a feedback mode to insure the divertor peak heat flux remains below an acceptable level, providing the first line of defense against excessive divertor heat loads which could result in damage to divertor PFCs. Moreover, the low confinement property of the divertor (i.e., <1 ms for Li particle confinement time) makes the ARLLD response fast enough to mitigate the effects of possible transient events such as large ELMs.     

Calcium: A comprehensive review on quantification,interaction with milk proteins and implications for processing of dairy products

Calcium (Ca) is a key micronutrient of high relevance for human nutrition that also influences the texture and taste of dairy products and their processability. In bovine milk, Ca is presented in several speciation forms, such as complexed with other milk components or free as ionic calcium while being distributed between colloidal and serum phases of milk. Partitioning of Ca between these phases is highly dynamic and influenced by factors, such as temperature, ionic strength, pH, and milk composition. Processing steps used during the manufacture of dairy products, such as preconditioning, concentration, acidification, salting, cooling, and heating, all contribute to modify Ca speciation and partition, thereby influencing product functionality, product yield, and fouling of equipment. This review aims to provide a comprehensive understanding of the influence of Ca partition on dairy products properties to support the development of kinetics models to reduce product losses and develop added-value products with improved functionality. To achieve this objective, approaches to separate milk phases, analytical approaches to determine Ca partition and speciation, the role of Ca on protein–protein interactions, and their influence on processing of dairy products are discussed.     

Identification of the Primary Factors Determining the Specificity of Human VKORC1 Recognition by Thioredoxin-Fold Proteins

Redox (reduction–oxidation) reactions control many important biological processes in all organisms, both prokaryotes and eukaryotes. This reaction is usually accomplished by canonical disulphide-based pathways involving a donor enzyme that reduces the oxidised cysteine residues of a target protein, resulting in the cleavage of its disulphide bonds. Focusing on human vitamin K epoxide reductase (hVKORC1) as a target and on four redoxins (protein disulphide isomerase (PDI), endoplasmic reticulum oxidoreductase (ERp18), thioredoxin-related transmembrane protein 1 (Tmx1) and thioredoxin-related transmembrane protein 4 (Tmx4)) as the most probable reducers of VKORC1, a comparative in-silico analysis that concentrates on the similarity and divergence of redoxins in their sequence, secondary and tertiary structure, dynamics, intraprotein interactions and composition of the surface exposed to the target is provided. Similarly, hVKORC1 is analysed in its native state, where two pairs of cysteine residues are covalently linked, forming two disulphide bridges, as a target for Trx-fold proteins. Such analysis is used to derive the putative recognition/binding sites on each isolated protein, and PDI is suggested as the most probable hVKORC1 partner. By probing the alternative orientation of PDI with respect to hVKORC1, the functionally related noncovalent complex formed by hVKORC1 and PDI was found, which is proposed to be a first precursor to probe thiol–disulphide exchange reactions between PDI and hVKORC1.     

Applications of percolation theory to fungal spread with synergy

There is increasing interest in the use of the percolation paradigm to analyse and predict the progress of disease spreading in spatially structured populations of animals and plants. The wider utility of the approach has been limited, however, by several restrictive assumptions, foremost of which is a strict requirement for simple nearest-neighbour transmission, in which the disease history of an individual is influenced only by that of its neighbours. In a recent paper, the percolation paradigm has been generalized to incorporate synergistic interactions in host infectivity and susceptibility, and the impact of these interactions on the invasive dynamics of an epidemic has been demonstrated. In the current paper, we elicit evidence that such synergistic interactions may underlie transmission dynamics in real-world systems by first formulating a model for the spread of a ubiquitous parasitic and saprotrophic fungus through replicated populations of nutrient sites and subsequently fitting and testing the model using data from experimental microcosms. Using Bayesian computational methods for model fitting, we demonstrate that synergistic interactions are necessary to explain the dynamics observed in the replicate experiments. The broader implications of this work in identifying disease-control strategies that deflect epidemics from invasive to non-invasive regimes are discussed.     

Dislocation interactions with grain boundaries

Recent progress in understanding dislocation interactions with grain boundaries and interfaces in metallic systems via static and in situ dynamic experimental approaches is reviewed.     

The collision efficiency of small bubbles with large particles

Bubble–particle interactions play an important role in many technological processes, e.g., in flotation. Although mineral flotation involves fine particles, this work focuses on the interactions between a small bubble and larger spherical particle and determining their collision efficiency. Based on the theoretical and experimental work, a simple relation for estimating the collision efficiency is proposed. The calculated efficiencies are compared to a large set of experimental data and are found to be in excellent agreement.     

Chemically Synthesized 58‐mer LysM Domain Binds Lipochitin Oligosaccharide

Recognition of carbohydrates by proteins is a ubiquitous biochemical process. In legume–rhizobium symbiosis, lipochitin oligosaccharides, also referred to as nodulation (nod) factors, function as primary rhizobial signal molecules to trigger root nodule development. Perception of these signal molecules is receptor mediated, and nod factor receptor 5 (NFR5) from the model legume Lotus japonicus is predicted to contain three LysM domain binding sites. Here we studied the interactions between nod factor and each of the three NFR5 LysM domains, which were chemically synthesized. LysM domain variants (up to 58 amino acids) designed to optimize solubility were chemically assembled by solid‐phase peptide synthesis (SPPS) with microwave heating. Their interaction with nod factors and chitin oligosaccharides was studied by isothermal titration calorimetry and circular dichroism (CD) spectroscopy. LysM2 showed a change in folding upon nod factor binding, thus providing direct evidence that the LysM domain of NFR5 recognizes lipochitin oligosaccharides. These results clearly show that the L. japonicus LysM2 domain binds to the nod factor from Mesorhizobium loti, thereby causing a conformational change in the LysM2 domain. The preferential affinity for nod factors over chitin oligosaccharides was demonstrated by a newly developed glycan microarray. Besides the biological implications, our approach shows that carbohydrate binding to a small protein domain can be detected by CD spectroscopy.     

Modal decomposition for the analysis of the rotor-stator interactions in multistage compressors

A modal analysis method of the rotor-stator interactions in multistage compressors has been developed by LMFA.This method,based on a double modal decomposition of the flow over space and time,has been applied to nu-merical and experimental results of the high-speed 3?-stage compressor CREATE based at LMFA,Lyon-France.It reveals the presence of a very strong rotor-stator interaction which completely drives the flow at casing behind all the rotors.This modal analysis method applied to an unsteady RANS simulation permits to calculate the en-ergy of the rotor-stator interactions and to plot energetic meridian maps to explain experimental results and to analyze the interaction in the whole machine.     

Electron correlation effects on polarons recombination in coupled polymer chains

The recombination dynamics of singlet and triplet oppositely charged polarons under the influence of electron–electron (e–e) interactions in coupled polymer chains are investigated using a multi-configurational time-dependent Hartree–Fock (MCTDHF) method. During recombination processes, singlet and triplet intrachain excitons are important products. By calculating the yields of the singlet and triplet intrachain excitons as a function of the on-site and long-range e–e interactions, it is found that the yields of the singlet and triplet intrachain excitons both decrease with increasing on-site e–e interactions. On the other hand, as the long-range e–e interactions increase, the yields of singlet intrachain excitons initially increase and then maintain a constant value, while the yields of the triplet intrachain excitons decrease. Our results show that the long-range e–e interaction is of fundamental importance and improves the luminescence efficiency in coupled polymer chains. Finally, the influence of the polymer chain length on the yields of singlet and triplet intrachain excitons is discussed.