Conformational variation in enzyme catalysis: A structural study on catalytic residues

Conformational variation in catalytic residues can be captured as alternative snapshots in enzyme crystal structures. Addressing the question of whether active site flexibility is an intrinsic and essential property of enzymes for catalysis, we present a comprehensive study on the 3D variation of active sites of 925 enzyme families, using explicit catalytic residue annotations from the Mechanism and Catalytic Site Atlas and structural data from the Protein Data Bank. Through weighted pairwise superposition of the functional atoms of active sites, we captured structural variability at single-residue level and examined the geometrical changes as ligands bind or as mutations occur. We demonstrate that catalytic centres of enzymes can be inherently rigid or flexible to various degrees according to the function they perform, and structural variability most often involves a subset of the catalytic residues, usually those not directly involved in the formation or cleavage of bonds. Moreover, data suggest that 2/3 of active sites are flexible, and in half of those, flexibility is only observed in the side chain. The goal of this work is to characterise our current knowledge of the extent of flexibility at the heart of catalysis and ultimately place our findings in the context of the evolution of catalysis as enzymes evolve new functions and bind different substrates.

Natural Bioactive Cinnamoyltyramine Alkylamides and Co-Metabolites

Natural products are a vital source for agriculture, medicine, cosmetic and other fields. Among them alkylamides are a broad and expanding group found in at least 33 plant families. Frequently, they possess a simple carbon skeleton architecture but show broad structural variability and important properties such as immunomodulatory, antimicrobial, antiviral, larvicidal, insecticidal and antioxidant properties, amongst others. Despite to these several and promising biological activities, up to today, only two reviews have been published on natural alkylamides. One focuses on their potential pharmacology application and their distribution in the plant kingdom and the other one on the bioactive alkylamides specifically found in Annona spp. The present review is focused on the plant bioactive cinnamoyltyramine alkylamides, which are subject of several works reported in the literature. Furthermore, the co-metabolites isolated from the same natural sources and their biological activities are also reported.

Structural variability and concerted motions of the T cell receptor - CD3 complex

We investigate the structural and orientational variability of the membrane-embedded T cell receptor (TCR) - CD3 complex in extensive atomistic molecular dynamics simulations based on the recent cryo-EM structure determined by Dong et al. (2019). We find that the TCR extracellular (EC) domain is highly variable in its orientation by attaining tilt angles relative to the membrane normal that range from 15° to 55°. The tilt angle of the TCR EC domain is both coupled to a rotation of the domain and to characteristic changes throughout the TCR - CD3 complex, in particular in the EC interactions of the C_ FG loop of the TCR, as well as in the orientation of transmembrane helices. The concerted motions of the membrane-embedded TCR - CD3 complex revealed in our simulations provide atomistic insights on conformational changes of the complex in response to tilt-inducing forces on antigen-bound TCRs.

LCAO Electronic Structure of Nucleic Acid Bases and Other Heterocycles and Transfer Integrals in B-DNA, Including Structural Variability

To describe the molecular electronic structure of nucleic acid bases and other heterocycles, we employ the Linear Combination of Atomic Orbitals (LCAO) method, considering the molecular wave function as a linear combination of all valence orbitals, i.e., 2s, 2px, 2py, 2pz orbitals for C, N, and O atoms and 1s orbital for H atoms. Regarding the diagonal matrix elements (also known as on-site energies), we introduce a novel parameterization. For the non-diagonal matrix elements referring to neighboring atoms, we employ the Slater–Koster two-center interaction transfer integrals. We use Harrison-type expressions with factors slightly modified relative to the original. We compare our LCAO predictions for the ionization and excitation energies of heterocycles with those obtained from Ionization Potential Equation of Motion Coupled Cluster with Singles and Doubles (IP-EOMCCSD)/aug-cc-pVDZ level of theory and Completely Normalized Equation of Motion Coupled Cluster with Singles, Doubles, and non-iterative Triples (CR-EOMCCSD(T))/aug-cc-pVDZ level of theory, respectively, (vertical values), as well as with available experimental data. Similarly, we calculate the transfer integrals between subsequent base pairs, to be used for a Tight-Binding (TB) wire model description of charge transfer and transport along ideal or deformed B-DNA. Taking into account all valence orbitals, we are in the position to treat deflection from the planar geometry, e.g., DNA structural variability, a task impossible for the plane Hückel approach (i.e., using only 2pz orbitals). We show the effects of structural deformations utilizing a 20mer evolved by Molecular Dynamics.

Studying the effect of alpha-synuclein and Parkinson’s disease linked mutants on inter pathway connectivities

Parkinson’s disease is a common neurodegenerative disease. The differential expression of alpha-synuclein within Lewy Bodies leads to this disease. Some missense mutations of alpha-synuclein may resultant in functional aberrations. In this study, our objective is to verify the functional adaptation due to early and late-onset mutation which can trigger or control the rate of alpha-synuclein aggregation. In this regard, we have proposed a computational model to study the difference and similarities among the Wild type alpha-synuclein and mutants i.e., A30P, A53T, G51D, E46K, and H50Q. Evolutionary sequence space analysis is also performed in this experiment. Subsequently, a comparative study has been performed between structural information and sequence space outcomes. The study shows the structural variability among the selected subtypes. This information assists inter pathway modeling due to mutational aberrations. Based on the structural variability, we have identified the protein–protein interaction partners for each protein that helps to increase the robustness of the inter-pathway connectivity. Finally, few pathways have been identified from 12 semantic networks based on their association with mitochondrial dysfunction and dopaminergic pathways.

Capturing the structural and compositional variability of Opalinus Clay: constraints from multidisciplinary investigations of Mont Terri drill cores (Switzerland)

Opalinus Clay is considered a potential host rock for radioactive waste disposal. The Jurassic claystone formation is composed of several facies and subfacies types, which are characterized by varying amounts of quartz, carbonates (cements and fossils) and clay minerals. To provide samples for ongoing experimental and numerical studies, a complete core section was drilled in the Mont Terri rock laboratory. The lithological and structural variability (including tectonic fault structures) from borehole BAD-2 was investigated using a multidisciplinary approach including high-resolution geoelectric in situ borehole measurements, mineralogical/geochemical and (micro)structural analyses.The lithological–compositional variability was captured by successfully applying a modified subfacies approach, which is independently confirmed by the geochemical data and ERT (Electrical Resistivity Tomography) measurements. The variability on the cm to dm scale perpendicular to bedding can be determined based on the mean resistivity and variation of amplitude. In particular, the facies transitions could be precisely located. The new results suggest that both shaly facies types form the homogenous part of the investigated section, whereas the sandy facies and especially the carbonate-rich sandy facies represent the more heterogeneous lithofacies types of the Opalinus Clay. The varying resistivity can be attributed to differences in clay mineral and carbonate content. Regarding the structural variability, brittle faults were observed with varying frequency throughout the investigated section. Most fault planes occur in the shaly facies types, some of them concentrate along heterogeneities on the subfacies scale. The striking reproducibility of the measurements and observations was confirmed by a comparison with boreholes drilled in parallel, indicating a rather low compositional–structural variability parallel to bedding. The applied multidisciplinary approach is well suited to depict the vertical and lateral variability of a claystone formation, allowing an assessment of the degree of homogeneity/heterogeneity based on the subfacies concept.

Studying the Effect of Alpha-Synuclein and Parkinson's Disease Linked Mutants on Inter Pathway Connectivities

Parkinson's Disease is a common neurodegenerative disease. The differential expression of alpha-synuclein within Lewy Bodies leads to this disease. Some missense mutations of alpha-synuclein may resultant in functional aberrations. In this study, our objective is to verify the functional adaptation due to early and late-onset mutation which can trigger or control the rate of alpha-synuclein aggregation. In this regard, we have proposed a computational model to study the difference and/or similarities among the Wild type alpha-synuclein and two mutations G51D and E46K which are responsible for slow and fast aggregation respectively. Evolutionary sequence space analysis is also performed in this experiment. Subsequently, a comparative study has been performed between structural information and sequence space outcomes. The study shows the structural variability among the selected subtypes. This information assists inter pathway modeling due to mutational aberrations. Based on the structural variability, we have identified the protein-protein interaction partners for each protein that helps to increase the robustness of the inter-pathway connectivity. As per the inter-pathway networks, drug addiction has clear impacts on both the mutations i.e., G51D-slow, and E46K-fast and can be considered as the reason for early-onset Parkinson’s Disease. Finally, three top pathways associated with drug addiction viz., Amphetamine addiction, alcoholism, and Cocaine addiction show the higher influence in the mutated pathway networks based on the PageRank Algorithm where Dopaminergic Synapse system is also found within the same list in terms of Parkinson’s Disease pathogenicity.