The Geogenomic Mutational Atlas of Pathogens (GoMAP) web system.

We present a new approach for pathogen surveillance we call Geogenomics. Geogenomics examines the geographic distribution of the genomes of pathogens, with a particular emphasis on those mutations that give rise to drug resistance. We engineered a new web system called Geogenomic Mutational Atlas of Pathogens (GoMAP) that enables investigation of the global distribution of individual drug resistance mutations. As a test case we examined mutations associated with HIV resistance to FDA-approved antiretroviral drugs. GoMAP-HIV makes use of existing public drug resistance and HIV protein sequence data to examine the distribution of 872 drug resistance mutations in ∼ 502,000 sequences for many countries in the world. We also implemented a broadened classification scheme for HIV drug resistance mutations. Several patterns for geographic distributions of resistance mutations were identified by visual mining using this web tool. GoMAP-HIV is an open access web application available at http://www.bio-toolkit.com/GoMap/project

The HIVToolbox 2 web system integrates sequence, structure, function and mutation analysis.

There is enormous interest in studying HIV pathogenesis for improving the treatment of patients with HIV infection. HIV infection has become one of the best-studied systems for understanding how a virus can hijack a cell. To help facilitate discovery, we previously built HIVToolbox, a web system for visual data mining. The original HIVToolbox integrated information for HIV protein sequence, structure, functional sites, and sequence conservation. This web system has been used for almost 40,000 searches. We report improvements to HIVToolbox including new functions and workflows, data updates, and updates for ease of use. HIVToolbox2, is an improvement over HIVToolbox with new functions. HIVToolbox2 has new functionalities focused on HIV pathogenesis including drug-binding sites, drug-resistance mutations, and immune epitopes. The integrated, interactive view enables visual mining to generate hypotheses that are not readily revealed by other approaches. Most HIV proteins form multimers, and there are posttranslational modification and protein-protein interaction sites at many of these multimerization interfaces. Analysis of protease drug binding sites reveals an anatomy of drug resistance with different types of drug-resistance mutations regionally localized on the surface of protease. Some of these drug-resistance mutations have a high prevalence in specific HIV-1 M subtypes. Finally, consolidation of Tat functional sites reveals a hotspot region where there appear to be 30 interactions or posttranslational modifications. A cursory analysis with HIVToolbox2 has helped to identify several global patterns for HIV proteins. An initial analysis with this tool identifies homomultimerization of almost all HIV proteins, functional sites that overlap with multimerization sites, a global drug resistance anatomy for HIV protease, and specific distributions of some DRMs in specific HIV M subtypes. HIVToolbox2 is an open-access web application available at [http://hivtoolbox2.bio-toolkit.com]

Drug Binding Site structure window and table.

<p><b>A</b>. Drug Binding Site structure window showing the structure of HIV protease:Saquinavir complex (1C6Z) with drug binding site for Saquinavir colored. The coloring scheme for the DRMs is as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0098810#pone-0098810-g002" target="_blank"><b>Fig. 2</b></a> with an additional color for binding site residues that do not have a known DRM (orange). <b>B</b>. Information for each Drug Binding Site Residue is shown in a table that is color-coded using the same coloring scheme. A distance threshold between atoms of the drug and atoms of the protein (2.5–4.0 Å) can be set using a pulldown menu; 4.0 Å was set in this figure. This table provides the chain:position of the amino acid, distance, whether it is a DRM, and the type of DRM. The first column of this sortable table is interactive, where a mouse click identifies the amino acid in the structure of the Drug Binding Site window (<b>A</b>).</p

Drug Resistance Mutations structure window and table.

<p><b>A</b>. DRM structure window showing the structure of HIV protease:Saquinavir complex (1C6Z) with DRMs for Saquinavir colored. The coloring scheme for the DRMs is beneficial (green), beneficial set (dark green; not shown), primary (red), primary set (pink), secondary set (purple) <b>B</b>. Information for each DRM is shown in a table that is color coded using the same DRM coloring scheme. DRMs for different drugs can be loaded using the pulldown menu at the bottom of the table. This sortable table also provides the chain:position, mutated amino acid, and links to the abstracts of PubMed papers supporting the DRM. The first column of this table is interactive, where a mouse click identifies the amino acid in the structure of the DRM structure window (<b>A</b>).</p

HIVToolbox2 Data Statistics.

<p>HIVToolbox2 Data Statistics.</p

HIV Mutation distributions for protease in select HIV-1 Class M subtypes.

<p>*The reference sequence for HIV-1 protease is NP_705926.</p

Sequence display and log windows.

<p><b>A</b>. The Sequence window shows the sequence of the selected proteins with fonts colored by domain. Highlighted residues are for functional sites shown in the Color Key/Log window (<b>B</b>), which has hyperlinked entries. The PDB structure identifier is also shown here. Colored thick lines above the sequence show the residue mapping of different PDB structures onto the sequence. These can be selected to load different structures. A checkbox at the bottom enables display of individual chains. Figures under the sequence are for predicted or known minimotifs, which can be selected to display in a Structure window. The DxTVxE minimotif is selected and colored purple here. All hyperlinked information about each minimotif is shown in the Motif Key/Log window tab (<b>C</b>).</p

Epitope structure window and table.

<p>Epitope window showing the structure of protease:Saquinavir complex (1C6Z) with immune epitope KMIGGIGGFI colored green. Different positive immune epitopes for the loaded HIV protein from the IEDB can be selected using a pulldown menu on the top of the window that shows the IEDB id number and peptide sequence or from the sortable Epitopes Log table <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0098810#pone.0098810-Vita1" target="_blank">[25]</a>.</p

Multimerization of HIV proteins.

<p>*Bolded residues are known multimerization inhibitors.</p

Protease DRM landscape.

<p>A collection of DRM surface plots for HIV protease generated with HIVToolbox2. All plots are for a structure of Amprenavir (ball and stick) bound to one subunit of protease (1HPV, chain A). The top-left panel shows functional sites and the adjacent panel shows all known immune epitopes from the IEDB ids 32326, 40375, 64343, and 71361. All other panels show resistance to different FDA-approved HIV protease inhibitors. The last panel shows a compendium of DRMs identify regions of the protease with different types of DRMs. The coloring of DRMs is as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0098810#pone-0098810-g002" target="_blank"><b>Fig. 2</b></a>.</p