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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]

The structural arrangement and dynamical behavior of polymer chains confined between neutral solid planes is studied using molecular simulations techniques. The formation of polar as well as polar interactions between poly(epsi-caprolactone), PCL and the clay surfaces, which can significantly contribute to the polymer intercalation, is shown by calculations of the interaction energies between the various subsystems.

The study was conducted on the mechanism for the isomerization of HCN taking into account the hydrated nature of the cometary environment and supposes an interaction with a cold electron in the inner cometary plasma region. The results show that the efficiency of this HNC formation mechanism appears to be dependent on both water molecule and cold electron densities.

An ab initio study was done to know the cataylic model reaction for the HCN isomerization catalyzed by one, two, three and four water molecules. Mechanisms considering trihydration and tehrahydration were also characterized where the reaction energies were 0.51 and 0.48 eV.

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 alpha,alpha'-linked quinqui-, sexi- and septithiophenes substituted through ester links at their termini, by chiral oligo(ethylene oxide) chians carrying an alpha, beta, delta and epsi methyl are reported. The sign of 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 quinquethiphene to the septithiophene having the same side chain.

Intercalculated and exfoliated models of polymer nanocomposites based on poly(eta-caprolactone) and functionalized montmorillonite clay are studied. Intercalculates and exfoliated models are considered for probing the structural characteristics of the corresponding nanocomposites prepared by melt intercalculation and in situ polymerization, respectively.

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]

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]

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]

Heavy Chain Only Antibodies are specific to Camelid species. Despite the lack of the light chain variable domain, their heavy chain variable domain (VH) domain, named V H H or nanobody, has promising potential applications in research and therapeutic fields. The structural study of V H H is therefore of great interest. Unfortunately, considering the huge amount of sequences that might be produced, only about one thousand of V H H experimental structures are publicly available in the Protein Data Bank, implying that structural model prediction of V H H is a necessary alternative to obtaining 3D information besides its sequence. The present study aims to assess and compare the quality of predictions from different modelling methodologies. Established comparative & homology modelling approaches to recent Deep Learning-based modelling strategies were applied, i.e. Modeller using single or multiple structural templates, ModWeb, SwissModel (with two evaluation schema), RoseTTAfold, AlphaFold 2 and NanoNet. The prediction accuracy was evaluated using RMSD, TM-score, GDT-TS, GDT-HA and Protein Blocks distance metrics. Besides the global structure assessment, we performed specific analyses of Frameworks and CDRs structures. We observed that AlphaFold 2 and especially NanoNet performed better than the other evaluated softwares. Importantly, we performed molecular dynamics simulations of an experimental structure and a NanoNet predicted model of a V H H in order to compare the global structural flexibility and local conformations using Protein Blocks. Despite rather similar structures, substantial differences in dynamical properties were observed, which underlies the complexity of the task of model evaluation.Communicated by Ramaswamy H. Sarma.

Background: Drepanocytosis is a genetic blood disorder characterized by red blood cells that assume an abnormal, rigid, sickle shape. In the pathogenesis of vaso-occlusive crises of sickle cell disease, red blood cells bind to the endothelium and promote vaso-occlusion. At the surface of these sickle red blood cells, the overexpressed protein Lutheran strongly interacts with the Laminin 511/521. The aim of this study is to identify a PPI inhibitor with a high probability of binding to Lutheran for the inhibition of the Lutheran-Laminin 511/521 interaction., Methods: A virtual screening was performed with 395 601 compounds that target Lutheran. Prior validation of a robust docking and scoring protocol was considered on the protein CD80 because this protein has a binding site with similar topological and physico-chemical characteristics and it also has a series of ligands with known affinity constants. This protocol consisted of multiple filtering steps based on docked scores, molecular dynamics simulations, post-screening scores, and molecular properties., Results: A robust docking and scoring protocol was validated on the protein CD80 with the docking program DOCK6 and the secondary scoring function XSCORE. We identified four molecules for Lutheran that have good structural and physico-chemical properties., Conclusion: We took advantage of the similarities between the binding site of Lutheran and that of the protein CD80 to set up a robust docking and scoring protocol. Our protocol for primary scoring filtering, molecular dynamics simulation filtering, secondary scoring filtering, and molecular property filtering allows discarding most of the ligands with four compounds that are promising candidates for inhibiting the Lutheran-Laminin 511/521 interaction., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

A joint theoretical and experimental study of the electronic and structural properties of liquid crystalline metal-free phthalocyanines bearing a strong potential for charge and exciton transport has been performed. The synthesis of such compounds has been triggered by quantum chemical calculations showing that: (i) hole transport is favored in metal-free phthalocyanines by their extremely low reorganization energy (0.045 eV) and large electronic splittings; and (ii) the efficiency of energy transfer along the one-dimensional discotic stacks is weakly affected by rotational disorder due to the two-dimensional character of the molecules. We have synthesized two metal-free phthalocyanines with different branched aliphatic chains on the gram scale to allow for a full characterization of their solid-state properties. The two compounds self-organize in liquid crystalline mesophases, as evidenced by optical microscopy, differential scanning calorimetry, X-ray powder diffraction, and molecular dynamics simulations. They exhibit a columnar rectangular mesophase at room temperature and a columnar hexagonal mesophase at elevated temperature.