December 2009

Accelrys Discovery Studio Newsletter

News and Information	Discovery Studio 2.5.5 now available for download! Accelrys is presenting at the Cambridge Healthtech Institute’s "PEP Talk" conference Announcing the NEW DS Open Hour Support Sessions! and more...
DS Tips and Tricks	Quantitative Rotation
Featured Journal Articles	Molecular Determinants of Ligand Selectivity in a Vertebrate Odorant Receptor
DS Community Forum Highlight	Quench (Slow Cool) Dynamics
Script or Protocol of the Month	Color Binding Site by Electrostatic Potential

News and Information

• Discovery Studio 2.5.5 release now available for download

  This release is an update to DS 2.5 with many user requested scientific and performance enhancements including:

  • DS2.5.5 is upgraded to work with the 64 bit version of the Pipeline Pilot 7.5 server. This simplifies the installation process, as you no longer need to maintain both 32 and 64 bit versions, and helps you improve performance of processor heavy calculations.
  • MODELER is upgraded to version 9v7 and includes native 64 bit version of the package.
  • CHARMm is upgraded to version 35b1 and includes a native 64 bit version of the package.
  • New protocols Filter by Property and RCSB Structure Search have been added to allow a variety of advanced searches of the Protein Data Bank directly from the client.
  • A grid-based 3D QSAR method is available through a new protocol, Create 3D QSAR Model in QSAR. Visualization of favourable and unfavourable interactions is also produced as part of the final results.
  • The Dock Ligands (GOLD) protocol has been modified to support version 4.1 of GOLD.
  • An Example protocol is provided to calculate residue electrostatic energy for predicting protein stability and thermostability.
  • Notable usability enhancements include:
    • Two new Discovery Guides: Dock Ligands and Sketch and Align Molecules
    • A new tool panel for Superimpose Proteins
    • Updates to several protein and binding site analysis tools
    • Updates to Molecule Window and Sequence Window
    • Tooltips are available for contextual help throughout the client
    • Scripting enhancements include new methods for accessing plots and dendrogram views, creation of pi-interaction and rotatable bond monitors, and saving images from the Graphics View
  You can access this update from your ESD account or by visiting the product updates page on the Accelrys website: http://accelrys.com/downloads/updates/discovery-studio/index.html. Additional details about this release and installation instructions are available from the readme on the distribution. We hope that your research benefits from these updates and as we look forward to the next release, please don’t hesitate to provide us with your feedback. Our success is based upon your success!

 

• Accelrys is presenting at the Cambridge Healthtech Institute’s "PEP Talk" conference

Accelrys is a proud sponsor of the 9th annual Cambridge Healthtech Institute's PEP Talk conference. The show will be held at the Hotel Del Coronado in San Diego January 11-15. The conference brings leaders in protein science together from around the World. Accelrys will be presenting a talk on antibody modeling

Modeling the 3-Dimensional Structures of Antibody and their Interaction Interface to Antigen Shikha Varma-O’Brien, Life Sciences, Accelrys
Given the increased interest in protein therapeutics, significant efforts are put into engineering novel antibody sequences. Modeling antibody 3-dimensional structures and their binding to antigen can provide valuable information in designing antibody sequences. We will present Accelrys' methods in building antibody framework structures, construct and refine the six hypervariable loop regions and predicting the antibody-antigen binding interfaces.


• Announcing the NEW DS Open Hour Support Sessions!

We are pleased to offer a new support mechanism to our DS users -- LIVE INTERACTIVE, and FULL of COOL demos! The DS Open Hour is an informal webinar series hosted by Accelrys scientists to answer any questions you might have with regard to Discovery Studio. Details can be found here :
http://accelrys.com/products/discovery-studio/ds-open-hour.html Drop in any time you like within that hour and ask any DS question!

Tips & Tricks

Quantitative Rotation in Discovery Studio
The objects in a 3D window can be rotated using the arrow keys on your keyboard. Each press of the arrow key will rotate the objects by 10 degrees. If you hold the shift key down then the object is rotated by 1 degree. Rotation about the X-axis is controlled by the up and down arrows, rotation about the Y-axis is controlled by the left and right arrows. To restore the initial orientation press the Home key. Note that these rotations only change the viewing angle; if you want to update the xyz coordinates, then use the Structure>Update Coordinates command.

Featured Journal Article

In silico, In vitro, and In vivo - From a homology model to an active compound!

The authors of built homology models of a goldfish odorant receptor OR5.24 and zebrafish odorant receptor Z06 using Modeler in order to understand the causes of odorant specificity in the goldfish odorant receptor 5.24 olfactory NTD receptor. The Zebrafish odorant receptor Z06 was identified as the most closely related c-family olfactory receptor to goldfish 5.24.

Based on the homology models of goldfish receptor 5.24, amino acid affinities were predicted using LigandFit docking and were consistent with binding assays.

This was also confirmed by functional activation assays. Goldfish receptor 5.24 shows a clear preference for basic versus acidic amino acids, whereas zebrafish receptor ZO6 was found to have the opposite preference despite their 73% sequence identity. These differences are explained in terms of interactions in the distal portion of the binding pocket of the receptors.

These predictions were refined by inclusion of in-silico and experimental site directed mutagenesis. This study shows the use of a homology models, and ligand docking studies to make predictions that are then validated by cloning and site directed mutagenesis/functional assays. Optional: In a further demonstration of the validity of the receptor 5.24 structural model, this model was used as the basis for an in silico high-throughput screen in which novel compounds -- showing activity both on the receptor and also on olfactory responses in vivo -- were identified (Triballeau et al., Neuron 2008).

1) Percy Luu, Francine Acher, Hugues-Olivier Bertrand, Jinhong Fan, and John Ngai
The Journal of Neuroscience, 2004, 24(45), 10128 –10137 Molecular Determinants of Ligand Selectivity in a Vertebrate Oderant Receptor

2) 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. High-potency olfactory receptor agonists discovered by virtual high-throughput screening: molecular probes for receptor structure and olfactory function.

 

Community Forum Highlight

Quench (Slow Cool) Dynamics
Simulated annealing is a robust method to obtain a low energy conformer. This technique involves using molecular dynamics to slowly cooling a system that has previously been equilibrated at some elevated temperature. A protocol has been created that extends the Dynamics (Heating and Cooling) protocol so that it can be used for this purpose. This protocol has been extended by allowing a CHARMm restart file (.rst) as input to the run. These restart files can be generated by all Simulation protocols. The restart file includes the final xyz coordinates and velocities of each atom, among other information. When using the "Dynamics (Heating and Cooling) with Restart" protocol ff the Target temperature is lower than the Initial Temperature then the protocol will slowly cool the system to the target temperature. The initial temperature should match the temperature that the system has been equilibrated to, for example, using the Dynamics (Equilibration) or Standard Dynamics Cascade protocol. The cooling temperature increment (or decrement) is 7.5 degrees, which is the recommended rate of cooling. If the final temperature is of critical importance be sure to turn on the option to save a restart file when the job completes so that the annealing can be continued if necessary. The protocol can be downloaded here.

Script of the Month

Color Binding Site by Electrostatic Potential
The script finds the nearest electrostatic grid point to each binding site point and colors it according to the potential value of that grid point. An atom is created at each binding site point, these atoms are then set to the desired color. The technique is useful to visualize the 3D electrostatic potential in anything from a small binding site to a porin channel. One domain of 2zfg, and OmpF porin, is shown below. The script can be downloaded here.

Give us your feedback. Tell us what you would like to hear about by dropping an email to: discovery@accelrys.com