POLYVIEW-MM: web-based platform for animation and analysis of molecular simulations

Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA.
Nucleic Acids Research (Impact Factor: 8.81). 07/2010; 38(Web Server issue):W662-6. DOI: 10.1093/nar/gkq445
Source: PubMed

ABSTRACT Molecular simulations offer important mechanistic and functional clues in studies of proteins and other macromolecules. However, interpreting the results of such simulations increasingly requires tools that can combine information from multiple structural databases and other web resources, and provide highly integrated and versatile analysis tools. Here, we present a new web server that integrates high-quality animation of molecular motion (MM) with structural and functional analysis of macromolecules. The new tool, dubbed POLYVIEW-MM, enables animation of trajectories generated by molecular dynamics and related simulation techniques, as well as visualization of alternative conformers, e.g. obtained as a result of protein structure prediction methods or small molecule docking. To facilitate structural analysis, POLYVIEW-MM combines interactive view and analysis of conformational changes using Jmol and its tailored extensions, publication quality animation using PyMol, and customizable 2D summary plots that provide an overview of MM, e.g. in terms of changes in secondary structure states and relative solvent accessibility of individual residues in proteins. Furthermore, POLYVIEW-MM integrates visualization with various structural annotations, including automated mapping of known inter-action sites from structural homologs, mapping of cavities and ligand binding sites, transmembrane regions and protein domains. URL:

  • [Show abstract] [Hide abstract]
    ABSTRACT: Recently, we reported on a potent benzimidazole derivative (227G) that inhibits the growth of the bovine viral diarrhea virus (BVDV) in cell-based and enzyme assays at nanomolar concentrations. The target of 227G is the viral RNA-dependent RNA polymerase (RdRp), and the I261M mutation located in motif I of the RdRp finger domain was found to induce drug resistance. Here we propose a molecular mechanism for the retained functionality of the enzyme in the presence of the inhibitor, on the basis of a thorough computational study of the apo and holo forms of the BVDV RdRp either in the wild type (wt) or in the form carrying the I261M mutation. Our study shows that although the mutation affects to some extent the structure of the apoenzyme, the functional dynamics of the protein appear to be largely maintained, which is consistent with the retained functionality of this natural mutant. Despite the binding site of 227G not collapsing or undergoing drastic structural changes upon introduction of the I261M substitution, these alterations reflect crucially on the binding mode of 227G, which is significantly different from that found in wt RdRp. In particular, while in the wt system the four loops lining the template entrance site embrace 227G and close the template passageway, in the I261M variant the template entrance is only marginally occluded, allowing in principle the translocation of the template to the interior of the enzyme. In addition, the mutated enzyme in the presence of 227G retains several characteristics of the wt apoprotein. Our work provides an original molecular picture of a resistance mechanism that is consistent with published experimental data.
    Biochemistry 10/2014; DOI:10.1021/bi500490z · 3.38 Impact Factor
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cytochrome P450 monooxygenases (P450s) are known to oxidize hydrocarbons albeit with limited substrate specificity across classes of these compounds. Here we report a P450 monooxygenase (CYP63A2) from the model ligninolytic white rot fungus Phanerochaete chrysosporium that was found to possess a broad oxidizing capability toward structurally diverse hydrocarbons belonging to mutagenic/carcinogenic fused-ring higher molecular weight polycyclic aromatic hydrocarbons (HMW-PAHs), endocrine-disrupting long-chain alkylphenols (APs), and crude oil aliphatic hydrocarbons n-alkanes. A homology-based 3D-model revealed presence of an extraordinarily large active site cavity in CYP63A2 compared to the mammalian PAH-oxidizing (CYP3A4, CYP1A2 and CYP1B1) and bacterial aliphatic hydrocarbon-oxidizing (CYP101D and CYP102A1) P450s. This structural feature in conjunction with ligand docking simulations suggested potential versatility of the enzyme. Experimental characterization using recombinantly expressed CYP63A2 revealed its ability to oxidize HMW-PAHs of varying ring size, including 4 rings (pyrene and fluoranthene), 5 rings [lsqb]benzo(a)pyrene[rsqb], and 6 rings [lsqb]benzo(ghi)perylene[rsqb]; the highest enzymatic activity being toward the 5-ring PAH followed by the 4-ring and 6-ring PAHs, in that order. CYP63A2 activity yielded monohydroxylated PAH metabolites. The enzyme was found to also act as an alkane ω-hydroxylase that oxidized varying chain-length n-alkanes (C9-C12 and C15-C19) as well as alkyl side-chains (C3-C9) in alkylphenols (APs). CYP63A2 showed preferential oxidation of long chain-length APs and alkanes. To our knowledge, this is the first of its kind P450 across biological kingdoms that possesses such broad substrate specificity toward structurally diverse xenobiotics (PAHs, APs, and alkanes), making it a potent enzyme biocatalyst candidate to handle mixed pollution (e.g., crude oil spills).
    Applied and Environmental Microbiology 02/2013; DOI:10.1128/AEM.03767-12 · 3.95 Impact Factor

Preview (2 Sources)

Available from