Introducing “best single template” models as reference baseline for the Continuous Automated Model Evaluation (CAMEO)

Critical blind assessment of structure prediction techniques is crucial for the scientific community to establish the state of the art, identify bottlenecks, and guide future developments. In Critical Assessment of Techniques in Structure Prediction (CASP), human experts assess the performance of participating methods in relation to the difficulty of the prediction task in a biennial experiment on approximately 100 targets. Yet, the development of automated computational modeling methods requires more frequent evaluation cycles and larger sets of data. The “Continuous Automated Model EvaluatiOn (CAMEO)” platform complements CASP by conducting fully automated blind prediction evaluations based on the weekly pre-release of sequences of those structures, which are going to be published in the next release of the Protein Data Bank (PDB). Each week, CAMEO publishes benchmarking results for predictions corresponding to a set of about 20 targets collected during a 4-day prediction window. CAMEO benchmarking data are generated consistently for all methods at the same point in time, enabling developers to cross-validate their method's performance, and referring to their results in publications. Many successful participants of CASP have used CAMEO—either by directly benchmarking their methods within the system or by comparing their own performance to CAMEO reference data. CAMEO offers a variety of scores reflecting different aspects of structure modeling, for example, binding site accuracy, homo-oligomer interface quality, or accuracy of local model confidence estimates. By introducing the "bestSingleTemplate" method based on structure superpositions as a reference for the accuracy of 3D modeling predictions, CAMEO facilitates objective comparison of techniques and fosters the development of advanced methods.     

Atomistic modelling of interface structure and deformation mechanisms in the Al/GaN multilayer under compression

The properties of ohmic contact and thermal boundary conductance between Al and GaN have been studied extensively, but the interface structures and deformation mechanisms in the Al/GaN multilayer can be rarely found in literatures. By molecular dynamics (MD) simulations, we systematically studied the interface structures and structural deformations in the Al/GaN multilayer. Two kinds of interface structures are identified according to the different terminal surfaces of GaN; glide-set terminal interface and shuffle-set terminal interface. Further analysis shows that interface has the maximum stress and misfit lines have the maximum stress values, which serve as the dislocation sources in the Al layer due to the larger stress in the interface. The mechanical responses of the Al/GaN multilayer exhibit a minor stage and some distinctive drops in the stress–strain curve. The first stage is associated with the dislocation nucleation from the interface. Upon further compression, more slip systems appear in the Al layer and dislocation nucleation in GaN could induce drops in curves. Meanwhile, the multiplications of dislocations cause strain hardening behaviours.     

Prediction of quaternary structure by analysis of hot spot residues in protein-protein interfaces: the case of anthranilate phosphoribosyltransferases

It is an important goal of computational biology to correctly predict the association state of a protein based on its amino acid sequence and the structures of known homologues. We have pursued this goal on the example of anthranilate phosphoribosyltransferase (AnPRT), an enzyme that is involved in the biosynthesis of the amino acid tryptophan. Firstly, known crystal structures of naturally occurring homodimeric AnPRTs were analyzed using the Protein Interfaces, Surfaces, and Assemblies (PISA) service of the European Bioinformatics Institute (EBI). This led to the identification of two hydrophobic “hot spot” amino acids in the protein-protein interface that were predicted to be essential for self-association. Next, in a comprehensive multiple sequence alignment (MSA), naturally occurring AnPRT variants with hydrophilic or charged amino acids in place of hydrophobic residues in the two hot spot positions were identified. Representative variants were characterized in terms of thermal stability, enzymatic activity, and quaternary structure. We found that AnPRT variants with charged residues in both hot spot positions exist exclusively as monomers in solution. Variants with hydrophilic amino acids in one hot spot position occur in both forms, monomer and dimer. The results of the present study provide a detailed characterization of the determinants of the AnPRT monomer-dimer equilibrium and show that analysis of hot spots in combination with MSAs can be a valuable tool in prediction of protein quaternary structures.     

Emergence,evolution, and vaccine production approaches of SARS-CoV-2 virus: Benefits of getting vaccinated and common questions

The emergence of coronavirus disease 2019 (COVID-19) pandemic in Wuhan city, China at the end of 2019 made it urgent to identify the origin of the causal pathogen and its molecular evolution, to appropriately design an effective vaccine. This study analyzes the evolutionary background of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or SARS-2) in accordance with its close relative SARS-CoV (SARS-1), which was emerged in 2002. A comparative genomic and proteomic study was conducted on SARS-2, SARS-1, and Middle East respiratory syndrome coronavirus (MERS), which was emerged in 2012. In silico analysis inferred the genetic variability among the tested viruses. The SARS-1 genome harbored 11 genes encoding 12 proteins, while SARS-2 genome contained only 10 genes encoding for 10 proteins. MERS genome contained 11 genes encoding 11 proteins. The analysis also revealed a slight variation in the whole genome size of SARS-2 comparing to its siblings resulting from sequential insertions and deletions (indels) throughout the viral genome particularly ORF1AB, spike, ORF10 and ORF8. The effective indels were observed in the gene encoding the spike protein that is responsible for viral attachment to the angiotensin-converting enzyme 2 (ACE2) cell receptor and initiating infection. These indels are responsible for the newly emerging COVID-19 variants αCoV, βCoV, γCoV and δCoV. Nowadays, few effective COVID-19 vaccines developed based on spike (S) glycoprotein were approved and become available worldwide. Currently available vaccines can relatively prevent the spread of COVID-19 and suppress the disease. The traditional (killed or attenuated virus vaccine and antibody-based vaccine) and innovated vaccine production technologies (RNA- and DNA-based vaccines and viral vectors) are summarized in this review. We finally highlight the most common questions related to COVID-19 disease and the benefits of getting vaccinated.     

Novel rhizobox design to assess rhizosphere characteristics at high spatial resolution

Available tools to study rhizosphere characteristics at a sub-mm spatial resolution suffer from a number of shortfalls, including geometrically and physiologically ill-defined root layers containing soil or other growth medium. Such designs may result in over- or underestimation of root-induced changes in the rhizosphere. We present a novel rhizobox design that overcomes these shortfalls. Plants are pre-grown in a soil–root compartment with an opening slit at the bottom. As plants reach the targeted physiological stage, this compartment is transferred on top of a rhizosphere soil compartment attached to a vertical root-only compartment. The latter is made up of a membrane (pore size 7 m to restrict root hair growth into the rhizosphere compartment or 30 m to restrict only root growth) and a transparent acrylic window which is gently pressed against the membrane and rhizosphere soil compartment using an adjustable screw. This design allows roots to penetrate from the upper soil–root compartment through the slit into the root-only compartment. Root growth and distribution can be monitored through the acrylic window using digital camera equipment. Upon termination of the experiment, the rhizosphere compartment is removed and frozen prior to separation of sub-mm soil layers using microtome techniques. In a test experiment, canola (Brassica napus L. cv. Sprinter) developed a fairly dense root monolayer within 8 days. Using measurement of soil characteristics at 0.5–1-mm increments across the rhizosphere we demonstrate that the proposed rhizobox design is yielding reproducible data. Due to exudation of LMWOC, we found a statistically significant increase of DOC towards the root plane, whereas more stable soil characteristics were not affected by root activity. Limitations and further extensions of this rhizobox design, including the use of micro suction cups and microsensors for pH and redox potential to measure spatial and temporal changes in a non-destructive manner are discussed along with potential applications such as validation of rhizosphere models.     

Functional behaviour of bone around dental implants

Achieving a long-term stable implant interface is a significant clinical issue when there is insufficient cortical bone stabilisation at implant placement. Clinical outcomes studies suggest that the higher risk implants are those placed in compromised cortical bone (thin, porous, etc.) in anatomical sites with minimal existing trabecular bone (characterised as type IV bone). In establishing and maintaining an implant interface in such an environment, one needs to consider the impact of masticatory forces, the response of bone to these forces and the impact of age on the adaptive capacity of bone. These forces, in turn, have the potential to create localised changes in interfacial stiffness through viscoelastic changes at the interface. Changes in bone as a function of age (e.g. localised hypermineralised osteopetrosis and localised areas of osteopenia) will alter the communication between osteocytes and osteoblasts creating the potential for differences in response of osteoblastic cells in the older population. A key to understanding the biomechanical and functional behaviour of implants in the older population is to control the anticipated modelling and remodelling behaviour through implant design that takes into account how tissues respond to the mechanically active environment.     

Specific DNA recognition by the Antp homeodomain: MD simulations of specific and nonspecific complexes

Four molecular dynamics simulation trajectories of complexes between the wild-type or a mutant Antennapedia homeodomain and 2 DNA sequences were generated in order to probe the mechanisms governing the specificity of DNA recognition. The starting point was published affinity measurements showing that a single protein mutation combined with a replacement of 2 base pairs yields a new high-affinity complex, whereas the other combinations, with changes on only 1 macromolecule, exhibited lower affinity. The simulations of the 4 complexes yielded fluctuating networks of interaction. On average, these networks differ significantly, explaining the switch of affinity caused by the alterations in the macromolecules. The network of mostly hydrogen-bonding interactions involving several water molecules, which was suggested both by X-ray and NMR structures of the wild-type homeodomain and its DNA operator sequence, could be reproduced in the trajectory. More interestingly, the high-affinity complex with alterations in both the protein and the DNA yielded again a dynamic but very tight network of intermolecular interactions, however, attributing a significantly stronger role to direct hydrophobic interactions at the expense of water bridges. The other 2 homeodomain-DNA complexes, with only 1 molecule altered, show on average over the trajectories a clearly reduced number of protein-DNA interactions. The observations from these simulations suggest specific experiments and thus close the circle formed by biochemical, structural, and computational studies. The shift from a water-dominated to a more "dry" interface may prove important in the design of proteins binding DNA in a specific manner.     

Beyond the rotamer library: genetic algorithm combined with the disturbing mutation process for upbuilding protein side-chains

The disturbing genetic algorithm, incorporating the disturbing mutation process into the genetic algorithm flow, has been developed to extend the searching space of side-chain conformations and to improve the quality of the rotamer library. Moreover, the growing generation amount idea, simulating the real situation of the natural evolution, is introduced to improve the searching speed. In the calculations using the pseudo energy scoring function of the root mean squared deviation, the disturbing genetic algorithm method has been shown to be highly efficient. With the real energy function based on AMBER force field, the program has been applied to rebuilding side-chain conformations of 25 high-quality crystallographic structures of single-protein and protein-protein complexes. The averaged root mean standard deviation of atom coordinates in side-chains and veracities of the torsion angles of chi(1) and chi(1) + chi(2) are 1.165 A, 88.2 and 72.9% for the buried residues, respectively, and 1.493 A, 79.2 and 64.7% for all residues, showing that the method has equal precision to the program SCWRL, whereas it performs better in the prediction of buried residues and protein-protein interfaces. This method has been successfully used in redesigning the interface of the Basnase-Barstar complex, indicating that it will have extensive application in protein design, protein sequence and structure relationship studies, and research on protein-protein interaction.     

Parameterization and classification of the protein universe via geometric techniques

We present a scheme for the classification of 3487 non-redundant protein structures into 1207 non-hierarchical clusters by using recurring structural patterns of three to six amino acids as keys of classification. This results in several signature patterns, which seem to decide membership of a protein in a functional category. The patterns provide clues to the key residues involved in functional sites as well as in protein-protein interaction. The discovered patterns include a "glutamate double bridge" of superoxide dismutase, the functional interface of the serine protease and inhibitor, interface of homo/hetero dimers, and functional sites of several enzyme families. We use geometric invariants to decide superimposability of structural patterns. This allows the parameterization of patterns and discovery of recurring patterns via clustering. The geometric invariant-based approach eliminates the computationally explosive step of pair-wise comparison of structures. The results provide a vast resource for the biologists for experimental validation of the proposed functional sites, and for the design of synthetic enzymes, inhibitors and drugs.     

Effects of aluminum sorption on calcium-polygalacturonate network used as soil-root interface model

The objective of this study is to determine the influence of aluminum sorption on a calcium-polygalacturonate (Ca-PG) network used as a soil-root interface model. The Ca-PG network is exposed to aluminum solutions at different concentrations (25-800 microM) at pH 3.50. High concentrations lead to a release of calcium (80%) and aluminum becomes the predominant reticulating cation of the polygalacturonic chains. The FTIR spectra show how aluminum sorption induces shifts of the characteristic bands of carbohydrates in the spectral regions of 1700-1400 and 1200-800 cm(-1), which are enhanced by decreasing intensities. This might be induced by a weakening of the metal-PG complex through conformational variations of the structure. Scanning electron micrographs also show a collapse of the fibrillar structure of Ca-PG that is due to aluminum sorption. This structural rearrangement suggests that the soil-root interface could modify its functionality, affecting the transport of metal ions (nutrients) across the interface and consequently through the cell membranes.