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With a view to explaining the structure-affinity properties of the ligands of the protein FKBP12, we characterized a binding intermediate state between this protein and a high-affinity ligand. Indeed, the nature and extent of the intermolecular contacts developed in such a species may play a role on its stability and, hence, on the overall association rate. To find the binding intermediate, a molecular simulation protocol was used to unbind the ligand by gradually decreasing the biasing forces introduced. The intermediate was subsequently refined with 17 independent stochastic boundary molecular dynamics simulations that provide a consistent picture of the intermediate state. In this state, the core region of the ligand remains stable, notably because of the two anchoring oxygen atoms that correspond to recurrent motifs found in all FKBP12 ligand core structures. Besides, the non-core regions participate in numerous transient intermolecular and intramolecular contacts. The dynamic aspect of most of the contacts seems important both for the ligand to retain at least a part of its configurational entropy and for avoiding a trapped state along the binding pathway. Since the transient and anchoring contacts contribute to increasing the stability of the intermediate, as a corollary, the dissociation rate constant of this intermediate should be decreased, resulting in an increase of the affinity constant . The present results support our previous conclusions and provide a coherent rationale for explaining the prevalence in high-affinity ligands of (i) the two oxygen atoms found in carbonyl or sulfonyl groups of dissimilar core structures and of (ii) symmetric or pseudo-symmetric mobile groups of atoms found as non-core moieties. Another interesting aspect of the intermediate is the distortion of the flexible 80 s loop of the protein, mainly in its tip region, that promotes the accessibility to the bound state. [ABSTRACT FROM AUTHOR]

Highlights: [•] We determine the force field parameters for two ligands. [•] Two high-affinity ligands of FKBP12 are considered. [•] Fitting procedure is based on quantum chemical calculations. [•] Attention is paid to the numerous dihedral angles of the ligands. [ABSTRACT FROM AUTHOR]

Abstract: The chloroplast protein CP12 is known to play a leading role in a complex formation with the enzymes GAPDH and PRK. As a preliminary step towards the understanding of the complex formation mechanism and the exact role of this protein linker, a comparative modelling of the CP12 protein of the green alga Chlamydomonas reinhardtii was performed. Because of the very few structural information and poor template similarities, the derivation of the model consisted in an iterative trial-and-error procedure using the comparative modelling program MODELLER, the following three structure validation programs PROCHECK, PROSA, and WHATIF, and molecular mechanics energy refinement of the model using the program CHARMM. The analysis of the final model reveals a scaffold of key residues that is believed to be essential in the folding mechanism and that coincides with the residues conserved throughout the CP12 family. Our results suggest that this protein is a typical disordered protein. Finally, the various mechanisms by which the CP12 protein can self-interact or binds to other enzymes are discussed in light of its modelled structure and characteristics. [Copyright &y& Elsevier]

Intercalated and exfoliated models of polymer nanocomposites based on poly(ε-caprolactone) and functionalized montmorillonite clay are studied by means of molecular dynamics simulations. Intercalated and exfoliated models are considered for probing the structural characteristics of the corresponding nanocomposites prepared by melt intercalation and in situ polymerization, respectively. In the exfoliated system, the organization of the polymer chains onto the clay surface is examined in terms of the density profiles and the order parameter function. A layered structure can clearly be seen to form near the surface with density maxima higher than in amorphous poly(ε-caprolactone). This can be viewed as an increase in effective particle thickness, which can contribute to the outstanding gas barrier properties of the exfoliated nanocomposites. The comparison of the structures and energetics of the intercalated model with those of a nanocomposite model based on a nonfunctionalized clay indicates nearly similar characteristics. Nevertheless, the slight differences observed for the interfacial polymer density and clay− and surfactant−polymer binding energies can account for the differences in rheological measurements. The results also suggest that the difference in morphology obtained for the nanocomposites prepared by the two synthetic approaches can be ascribed to both a difference in interfacial polymer density and the formation of bridging polymer chain structures that hinder the exfoliation process. [ABSTRACT FROM AUTHOR]

Abstract: The reaction of formaldehyde with ammonia to generate NH2CH2OH, an amino acid precursor, is studied at the CCSD(T)/6-311+G**//B3LYP/6-311+G** and CCSD(T)/6-311+G**//MP2/6-311+G** levels. The addition of one, two, and three water molecules is studied. Regardless, the reaction mechanism always consists of a nucleophilic attack of the carbon by the lone pair on the nitrogen accompanied by the simultaneous transfer of a proton to the formaldehyde oxygen. With water present, this proton transfer occurs via a chain of proton transfers. For one, and then two, water molecules, the activation energy is lowered. Addition of a third water molecule does not lower it further. [Copyright &y& Elsevier]

Abstract Phosphatidylinositide 3-kinases (PI3Ks) are widely expressed enzymes involved in membrane signalization pathways. Attempts to administer inhibitors with broad activity against different isoforms have failed due to toxicity. Conversely the PI3Kδ isoform is much more selectively expressed, enabling therapeutic targeting of this isoform. Of particular interest PI3Kδ is expressed in human basophils and its inhibition has been shown to reduce anti-IgE induced basophil degranulation, suggesting that PI3Kδ inhibitors could be useful as anti-allergy drugs. Herein, we report for the first time the activity of compounds derived from chalcone scaffolds as inhibitors of normal human basophil degranulation and identified the most active compound with anti-PI3Kδ properties that was investigated in preclinical models. Compound 18 , namely 1-[2-hydroxy-4,6-dimethoxy-3-(N -methylpiperidin-4-yl)phenyl]-3-(2,4,6-trimethoxyphenyl)-prop-2-en-1-one, was found to inhibit normal human basophil degranulation in a dose-dependent manner. In a murine model of ovalbumin-induced asthma, compound 18 was shown to reduce expiratory pressure while its impact on the inflammatory infiltrate in alveolar lavage and total lung was dependent on the route of administration. In a DNFB-induced model of atopic dermatitis compound 18 administered systemically proved to be as potent as topical betamethasone. These results support the anti-atopic and allergic properties of the title compound and warrant further clinical development. Graphical abstract Image 1 Highlights • Chalcones inhibit normal human basophil degranulation. • Piperidinyl unit contribute to the inhibition of the PI3Kδ isoform. • Reduction of expiratory pressure with piperidinyl-embeded chalcones. • Anti-atopic properties as potent as topical betamethasone. [ABSTRACT FROM AUTHOR]

Conformational flexibility plays an essential role in antibodies' functional and structural stability. They facilitate and determine the strength of antigen–antibody interactions. Camelidae express an interesting subtype of single-chain antibody, named Heavy Chain only Antibody. They have only one N-terminal Variable domain (VHH) per chain, composed of Frameworks (FRs) and Complementarity Determining regions (CDRs) like their VH and VL counterparts in IgG. Even when expressed independently, VHH domains display excellent solubility and (thermo)stability, which helps them to retain their impressive interaction capabilities. Sequence and structural features of VHH domains contributing to these abilities have already been studied compared to classical antibodies. To have the broadest view and understand the changes in dynamics of these macromolecules, large-scale molecular dynamics simulations for a large number of non-redundant VHH structures have been performed for the first time. This analysis reveals the most prevalent movements in these domains. It reveals the four main classes of VHHs dynamics. Diverse local changes were observed in CDRs with various intensities. Similarly, different types of constraints were observed in CDRs, while FRs close to CDRs were sometimes primarily impacted. This study sheds light on the changes in flexibility in different regions of VHH that may impact their in silico design. [ABSTRACT FROM AUTHOR]

VHH, i.e., VH domains of camelid single-chain antibodies, are very promising therapeutic agents due to their significant physicochemical advantages compared to classical mammalian antibodies. The number of experimentally solved VHH structures has significantly improved recently, which is of great help, because it offers the ability to directly work on 3D structures to humanise or improve them. Unfortunately, most VHHs do not have 3D structures. Thus, it is essential to find alternative ways to get structural information. The methods of structure prediction from the primary amino acid sequence appear essential to bypass this limitation. This review presents the most extensive overview of structure prediction methods applied for the 3D modelling of a given VHH sequence (a total of 21). Besides the historical overview, it aims at showing how model software programs have been shaping the structural predictions of VHHs. A brief explanation of each methodology is supplied, and pertinent examples of their usage are provided. Finally, we present a structure prediction case study of a recently solved VHH structure. According to some recent studies and the present analysis, AlphaFold 2 and NanoNet appear to be the best tools to predict a structural model of VHH from its sequence. [ABSTRACT FROM AUTHOR]

The synthesis, characterization, and self-assembly in butanol of a series of well-defined α,α'- linked quinqui-, sexi-, and septithiophenes substituted, via ester links at their termini, by chiral oligo(ethylene oxide) chains carrying an α, β, δ, and ϵ methyl, respectively, are reported. Studies of the self-assembly of these molecules using UV/visible absorption, luminescence, and circular dichroism spectroscopies reveal, for the sexithiophene case, that the magnitude of the observed Cotton effect in the aggregates diminishes progressively as the chiral substituent is moved away from the thiophene segment. The stability of the assemblies increases with the length of the oligothiophene and as the substituent chiral unit is moved away from the aromatic core, being greatest for the unsubstituted case. The sign of the Cotton effect alternates in an odd/even" manner as the position of the chiral substituent is moved along the oligo-(ethylene oxide) chain and on going from the quinquethiophene to the septithiophene having the same side chain. Atomic force microscopy on materials deposited from solution on an aluminum or glass surface and optical measurements show that capsules are formed from the oligothiophenes with H-type packing of the aromatic segments. [ABSTRACT FROM AUTHOR]