IgG1-b12-HIV-gp120 Interface in Solution: A Computational Study.

The use of broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) has been shown to be a promising therapeutic modality in the prevention of HIV infection. Understanding the b12-gp120 binding mechanism under physiological conditions may assist the development of more broadly effective antibodies. In this work, the main conformations and interactions between the receptor-binding domain (RBD) of spike glycoprotein gp120 of HIV-1 and the IgG1-b12 mAb are studied.

Tethering of the IgG1 Antibody to Amorphous Silica for Immunosensor Development: A Molecular Dynamics Study.

A key factor for improving the sensitivity and performance of immunosensors based on mechanical-plasmonic methods is the orientation of the antibody proteins immobilized on the inorganic surface. Although experimental techniques fail to determine surface phenomena at the molecular level, modern simulations open the possibility for improving our understanding of protein-surface interactions. In this work, replica exchange molecular dynamics (REMD) simulations have been used to model the IgG1 protein tethered onto the amorphous silica surface by considering a united-atom model and a relatively large system (2500 nm surface).

Conformational Dynamics Underlies Different Functions of Human KDM7 Histone Demethylases.

The human KDM7 subfamily histone H3 Nϵ-methyl lysine demethylases PHF8 (KDM7B) and KIAA1718 (KDM7A) have different substrate selectivities and are linked to genetic diseases and cancer. We describe experimentally based computational studies revealing that flexibility of the region linking the PHD finger and JmjC domains in PHF8 and KIAA1718 regulates interdomain interactions, the nature of correlated motions, and ultimately H3 binding and demethylation site selectivity. F279S an X-linked mental retardation mutation in PHF8 is involved in correlated motions with the iron ligands and second sphere residues.

Conformational flexibility influences structure-function relationships in nucleic acid N-methyl demethylases.

N-Methylation of DNA/RNA bases can be regulatory or damaging and is linked to diseases including cancer and genetic disorders. Bacterial AlkB and human FTO are DNA/RNA demethylases belonging to the Fe(ii) and 2-oxoglutarate oxygenase superfamily. Modelling studies reveal conformational dynamics influence structure-function relationships of AlkB and FTO, e.

Combined Quantum Mechanics and Molecular Mechanics Studies of Enzymatic Reaction Mechanisms.

The combined quantum mechanics/molecular mechanics (QM/MM) methods have become a valuable tool in computational biochemistry and received versatile applications for studying the reaction mechanisms of enzymes. The approach combines the calculations of the electronic structure of the active site by QM, with modeling of the protein environment using MM force field, which allows the long-range electrostatics and steric effects on the enzyme reactivity to be accounted for. In this review, we review some key theoretical and computational aspects of the method and we also present some applications to particular enzymatic reactions such as tryptophan-7-halogenase, cyclooxygenase-1, and the epidermal growth factor receptor.

Integrating molecular probes and molecular dynamics to reveal binding modes of GLUT5 activatory and inhibitory ligands.

Fructose transporter GLUT5 is characterized by unusual substrate specificity and is linked to a variety of metabolic disorders. A series of high-affinity GLUT5-specific sugar-based probes - ManCous - have been very recently described and efficiently used as reporters of GLUT5 activity in cells. Here we present several 1 microsecond molecular dynamics (MD) simulations of GLUT5 and its complexes with fructose and two different ManCou probes, in a solvated cell membrane environment.

Structural Insights from Molecular Dynamics Simulations of Tryptophan 7-Halogenase and Tryptophan 5-Halogenase.

Many natural organic compounds with pharmaceutical applications, including antibiotics (chlortetracycline and vancomycin), antifungal compounds (pyrrolnitrin), and chemotherapeutics (salinosporamide A and rebeccamycin) are chlorinated. Halogenating enzymes like tryptophan 7-halogenase (PrnA) and tryptophan 5-halogenase (PyrH) perform regioselective halogenation of tryptophan. In this study, the conformational dynamics of two flavin-dependent tryptophan halogenases-PrnA and PyrH-was investigated through molecular dynamics simulations, which are in agreement with the crystallographic and kinetic experimental studies of both enzymes and provide further explanation of the experimental data at an atomistic level of accuracy.

Fluorescent Probes for Sensitive and Selective Detection of pH Changes in Live Cells in Visible and Near-infrared Channels.

We report five fluorescent probes based on coumarin-hybridized fluorescent dyes with spirolactam ring structures (A-E) to detect pH changes in live cell by monitoring visible and near-infrared fluorescence changes. Under physiological or basic conditions, the fluorescent probes A, B, C, D and E preserve their spirolactam ring-closed forms and only display fluorescent peaks in the visible region corresponding to coumarin moieties at 497, 483, 498, 497 and 482 nm, respectively. However, at acidic pH, the rings of the spirolactam forms of the fluorescent probes A, B, C, D and E open up, generating new near-infrared fluorescence peaks at 711, 696, 707, 715, and 697 nm, respectively, through significantly extended π-conjugation to coumarin moieties of the fluorophores.

Targeting cancer-specific glycans by cyclic peptide lectinomimics.

The transformation from normal to malignant phenotype in human cancers is associated with aberrant cell-surface glycosylation. Thus, targeting glycosylation changes in cancer is likely to provide not only better insight into the roles of carbohydrates in biological systems, but also facilitate the development of new molecular probes for bioanalytical and biomedical applications. In the reported study, we have synthesized lectinomimics based on odorranalectin 1; the smallest lectin-like cyclic peptide isolated from the frog Odorrana grahami skin, and assessed the ability of these peptides to bind specific carbohydrates on molecular and cellular levels.

Luminescent Probes for Sensitive Detection of pH Changes in Live Cells through Two Near-Infrared Luminescence Channels.

Two water-soluble near-infrared luminescent probes, which possess both conventional intense Stokes fluorescence and unique single-photon frequency upconversion luminescence (FUCL), were developed for sensitive and selective detection of pH changes in live cells. The water solubility and biocompatibility of these probes were achieved by introducing mannose residues through 2,2'-(ethylenedioxy)diethylamine tethered spacers to a near-infrared conventional fluorescence (CF) and FUCL organic fluorophore. At a pH higher than 7.

Conformational Dynamics, Ligand Binding and Effects of Mutations in NirE an S-Adenosyl-L-Methionine Dependent Methyltransferase.

Heme d1, a vital tetrapyrrol involved in the denitrification processes is synthesized from its precursor molecule precorrin-2 in a chemical reaction catalysed by an S-adenosyl-L-methionine (SAM) dependent Methyltransferase (NirE). The NirE enzyme catalyses the transfer of a methyl group from the SAM to uroporphyrinogen III and serves as a novel potential drug target for the pharmaceutical industry. An important insight into the structure-activity relationships of NirE has been revealed by elucidating its crystal structure, but there is still no understanding about how conformational flexibility influences structure, cofactor and substrate binding by the enzyme as well as the structural effects of mutations of residues involved in binding and catalysis.