March 2009

Accelrys Discovery Studio Newsletter

News and Information

• The Accelrys 2009 User Group Meeting in San Diego in February drew
  over 100 customers and 13 of our software vendor partners. Talks were presented by researchers from BMS, Facet Biotech, Pfizer, NIEHS, U. Maryland, Synta Pharm., ACT LLC and others. Many customers took part in the pre-conference trainings and all took away a deeper knowledge of both Accelrys existing products and our plans for the future. Our thanks to all who helped make this event so successful! We hope to see you there next year.
• Virtual screening with GOLD* docking algorithm in Discovery Studio

  Discovery Studio (DS) architecture allows seamless and sophisticated integration of any third party algorithm. Discovery Studio has for several versions provided tight integration with the GOLD docking algorithm and allowed GOLD users to benefit from the robust features of Discovery Studio for model preparation and docking analysis.  GOLD, sold by CCDC, is a very widely used protein/ligand docking program with many publications demonstrating its value both in virtual Screening and in identifying likely binding modes of active molecules.  The integration of GOLD with Discovery Studio enhances the usability of GOLD for users familiar with DS, as docking runs can be set up and submitted without using the GOLD interface.  Through DS, GOLD users  have access to all the Discovery Studio Tools for protein model clean-up  and for ligand preparation prior to docking.  Furthermore, post-docking protocols such as in situ Ligand Minimization and Analyze Ligand Poses can be applied for analysis. (* requires license from CCDC ).

• A wide range of Webinar topics are available for free here.
• Life Sciences Product training: Accelrys training offerings are available here.

Tips & Tricks

How to generate the symmetry related chains required to form a biologically active protein.

PDB files will occasionally contain only part of the biologically active form of a protein. When this is the case they should contain the matrix information required to generate the full biologically active protein. Discovery Studio makes it very easy to apply this information and generate the full biologically active protein. For example, Load 3c02.pdb (File/Open URL...). After 3c02 is loaded into DS you can generate the missing parts using "Structure/Superimpose/Apply Transformation Matrix...". Any BIOMT transformation matrix defined in the pdb file can be applied. BIOMT_1 is the identity transform. Select BIOMT_2, verify that the "Create copy" option is on and then click OK. Repeat for BIOMT_3 and BIOMT_4. You now have generated the biologically active complex.

Featured Journal Article

High-potency olfactory receptor agonists discovered by virtual high-throughput screening: molecular probes for receptor structure and olfactory function.
The authors, Triballeau et al.used Pipeline Pilot® and Discovery Studio® identify agonists using a computational high-throughput screening strategy followed by pharmocophore screening and 3D docking to an olfactory G protein-coupled receptor. Functional validation of the top candidates confirmed that a significant fraction are active molecules, with several agonists exhibiting higher potencies than any of the receptor’s known natural ligands. The authors add, "Our virtual screening approach should be applicable to the identification of new bioactive molecules for probing the structure of chemosensory receptors and the function of chemo-sensory systems in vivo . "

Triballeau N, Van Name E, Laslier G, Cai D, Paillard G, Sorensen PW, Hoffmann R, Bertrand HO, Ngai J, Acher FC, Neuron, 2008 Dec 10;60(5):767-74.

Community Forum Highlight

The script SecStrList_trajectory.pl ("Residue based Secondary Structure list for all frames of a Trajectory") will let you monitor the secondary structure variations for each residue in a trajectory. The input can either be a protein with a trajectory in a Discovery Studio 3D window, or a series of frames saved as files. This script is adapted from "Tally Secondary Structure Elements of each Conformation in a Trajectory (DS 2.1)" which is also in the DiscoveryScript forums. This Discovery Script can be downloaded from the forums here.

Protocol of the Month

Analyze Protein-Ligand Complexes (Compare Binding Sites)

This protocol has several modes, but the end goal is to compare the binding site of one (reference) protein with putative binding sites in similar aligned proteins. The per residue RMSD values and chi values are reported for the aligned binding site residues. The Selection Method parameter provides the option to define the binding site as a set of residues OR let the protocol determine the residues from a selected Ligand and cutoff distance. The protocol can be accessed from our forums page here.

Binding Site Analysis in Discovery Studio
DS allows you to find binding pockets in a protein structure, visualize the cavities in custom views, and allows you to perform docking and de novo design experiments within the defined binding pocket. The image below shows a ligand binding region for a serine protease. The translucent solvent accessible surface is colored by electrostatic potential. The residues identified as "BindingSiteResidues" by the "Analyze Protein-Ligand Complexes" script have been highlighted with yellow bonds. Standard Discovery Studio Binding Site Analysis tools have been used to render different aspects of the active site. Donors (green), acceptors (purple) and hydrophobes (light-blue) regions were identified and colored using the "Define Interaction Site" function. The neighboring binding pocket was located using "Find Sites from Receptor Cavity" and has been colored with a transparent green shell.