Documentation for SiteMapper

  1. Introduction

    SiteMapper is a free webserver originally designed for computational evaluation of the binding site similarity of proteins and analysis of the residue correspondences based on 3Dstructure information. By means of structure-based alignment, SiteMapper is capable of detecting common patterns or residue reservation between binding sites which are not required to possess continuous residues or to be homologous. These common patterns can be further used to perform protein classification or reverse virtual screening, e.g.:

    • Predict a drug candidate’s off-target interactions;
    • Predict new target for known drugs;
    • Predict a protein’s function.

    Internally, the SiteMapper is implemented based on an in-house developed program which abstracts the input binding sites as backbones of alpha carbons and tries to align these 3D structures. The underlying alignment process is deviation induced and an efficient down-hill simplex algorithm is applied to search the optimal alignment which takes both the residue position and residue type into full consideration, while the residue correspondence is identified using a Hungarian algorithm based method. SiteMapper can be very useful for evaluating the binding site similarity or performing discontinuous sequence alignment for binding sites in a 3D manner.

  2. Submit Your Job

    1. Step 1, Prepare the Binding Sites

      In order to evaluate a pair of binding sites, user should provide a valid PDB code and identifiers of residues representing the binding sites for both reference and fit structures. The input interface includes the following fields to define a binding site:

      • PDB Code: Binding site will be defined in this structure;
      • Chain: Binding site will include residues in this chain;
      • Ligand: Binding site will include residues around this ligand;
      • Distance Cutoff: Binding site will include all residues within this distance;
      • Residue Identifier (Residue Selector): All residue selected will be part of the binding site.
      Of all the above mentioned fields, only PDB code and residue identifiers are required and other fields are all optional. SiteMapper provides an easy-to-use visual interface to simplify the input process. After a valid PDB code has been entered, the corresponding sequence and ligand information will be analyzed. By selecting specific items in “Chain”, “Ligand” and “Distance Cutoff” selector, it is very convenient to select residues within some distance around a ligand to represent a binding site. Further fine-grained addition or removal of residues can be performed in the sequence panel. All selected residues will be considered as part of the binding site and submitted for binding site similarity evaluation. Following a step-by-step guidance provided by SiteMapper, the data input process can be very easy and natural.

      Input Snapshot

      In order to define a binding site for subsequent similarity evaluation, the following operations should be performed:

      1. Enter a valid PDB code and click “Load” button to load the corresponding structure.
      2. After the PDB structure has been successfully loaded, click “Analyze” button to analyze related information. As a result, the residue selector will be rendered to assist defining a binding site.
      3. Select specific chain, ligand and distance cutoff in corresponding selector to define a binding site. Alternatively, you can ignore this step and choose to select binding site residues manually.
      4. Additional refinement could be performed by adding or removing binding site residues in the residue selector panel.

    2. Step 2, Submit the Job

      Once both the reference and fit binding site have been defined, it is ready to submit the job to evaluate the similarity. Click the “Submit” button to submit the job and the user will be automatically directed to a job status page which provides detailed information about a job. Of all the information displayed in the job status page, the most important one is the job ID which should be reserved by the user in order to query the status or get the result of a job.

      Submit Button Snapshot

      Note: If user provides an email address at the submission of a job, then a notification email will be sent to the corresponding address once the job is completed.

  3. Get Your Result

    1. Query Your Job

      Through the “Result” item in the navigation bar located at the top of main page, user can query the status of a job conveniently and view the result if the job is completed. Provide the job ID and corresponding email address if any, user will be directed to the job status page. The job status page displays detailed information about a job, e.g. current status of the jobs, links to view or download result. There are several possible statuses for a job, as follows:

      • Wait: The job is currently in a waiting queue to be scheduled due to too many simultaneous job submissions.
      • Running: The job is currently running and will be completed as soon as possible.
      • Complete: The job has been completed successfully and result is ready to be viewed online or downloaded.
      • Error: An error has occurred and a detailed log is provided.

      Navigation Bar Snapshot
      Job Status Snapshot

      Note: The job status page will automatically refresh itself to reflect the most recent status of the job.

    2. View Your Result

      From the job status page, the result of a job could be viewed once it is completed. The online output provided by SiteMapper is a visualization of the aligned binding sites along with the similarity score and the residue correspondences between the reference and query binding sites. Each residue correspondence could be highlighted and visualized in 3D mode freely by the user. Additionally, all result files (including files for both original and aligned structure, files containing residue correspondences and other information) are packaged and ready to be downloaded by user for performing further analysis locally.

      Output Snapshot