Last Wednesday, I was fortunate enough to be invited as a guest lecturer to the 3rd BioDataScience101 workshop, an initiative spearheaded by Paolo Marcatili, Professor of Bioinformatics at the Technical University of Denmark (DTU). This session, on amino acid sequence analysis applied to both proteomics and antibody drug discovery, was designed and organised by OPIG’s very own Tobias Olsen.
Continue readingMonthly Archives: November 2020
Doing rigid receptor docking? Consider using multiple structures!
Here it is. It’s finally happening. I’m actually writing a blog post about docking. Are the end times upon us? Perhaps. If by my next post I’m not back to my usual techie self, the horsemen may well be on their way.
If you’ve ever used, read about, or listened to a lab mate complain about protein-ligand docking, you’re likely familiar with the rigid receptor assumption. In this model, the active site of the protein is treated as completely rigid, with no side chain flexibility, and only the rotatable bonds in the ligand are allowed to move. The motivation behind this assumption is simple. The computational cost of sampling the conformational space of a ligand within a protein’s active site, and doing so with sufficient rigour so as to sample a near-native binding mode, grows rapidly with the number of rotatable bonds in the ligand. Further increasing the degrees of freedom in the system by incorporating receptor side chain flexibility compounds this problem, making the sampling of accurate binding modes for the ligand an incredibly expensive and difficult problem.
One compromise, if multiple structures with different active site conformations are available for the target protein, is to simply dock your ligands into multiple structures, and trust your scoring function (!!!) to pick out the best binding mode from across the different structures. This is a crude approximation to true flexible receptor docking which won’t capture fully any induced fit effects due to a particular ligand, but if the structures are available, this may offer a more computationally-feasible alternative to flexible docking.
A study earlier this year by Cleves and Jain illustrates this approach nicely. They dock the ligands of the DUD-E database into multiple structures for each target, in each case treating the receptor strucutre as completely rigid. Unsurprisingly, when the target is rigid and there is little structural variation in the active site across the structures, the choice of structure has little influence on the docking results. However, when the receptor is flexible, with clear structural variation across the active sites in the different structures, there is a strong impact on the poses generated by rigid-receptor docking. This effect translates directly into improved virtual screening performance when docking into multiple different structures, illustrating the value of considering the conformational space of the receptor, even when it is treated as rigid during the docking process.
PyMOL: colour by residue
PyMOL is a handy free way of viewing three dimensional protein structures. It allows you to toggle between different representations of the protein – such as cartoon, surface, sticks, etc. – which all have their own pros and cons.
However one thing I felt that PyMOL lacked was an easy way to visually distinguish residues based on type. Whist you can easily differentiate atom types based on colour in the colour menu, and even choose which colour you wish carbons to show up as whilst keeping heteroatoms different colours, this assigned carbon colour would be constant throughout the entire protein.
Enhance your presentation by using virtual webcams and scene transitions
If you haven’t checked out Matt’s post on using OBS for recording video, I highly recommend doing so. OBS is a terrific way to present your work online. It can provide (amongst many, many other things) the ability to create live picture-in-picture scenes, so you can move through your powerpoint deck whilst overlaying video of your tiny talking head in the corner.
Continuing on from Matt’s post, I’d like to promote the OBS virtual camera plugin and Touch Portal.
Every company, department or course has its own favourite video conferencing application and whilst they all have their strengths, consistency is not one of them. If you want to consistently display your presentation and your live video regardless of the platform in use, this quickly gets into the “messy” territory. This is where the virtual camera comes in.
Graphical abstracts that spark joy on a gloomy day
Have you ever read a paper just because it had a funny, endearing, or utterly bizarre graphical abstract? Ever since a colleague showed me the ‘Graphical abstracts that I gone and found’ Facebook page, I have definitely come across a few, and I thought I would share some of my favourite ones below. If you enjoy this kind of thing, I strongly suggest visiting their page for more – it makes for a wonderful distraction from pretty much anything. Continue reading
Using Python in PyMOL
Decades later, we owe Warren DeLano and his commitment to open source a great debt. Warren wrote PyMOL, an amazingly powerful and popular molecular visualization tool, but it has many hidden talents.
Perhaps its greatest strength is the use of the open source language, Python, as its control language.
Continue readingBuilding More Useful Bash Scripts
If there is some set of keystrokes that you find yourself using day in, day out, you can almost certainly write something that can automate the process. This could be something simple that could be achieved by putting a bash alias somewhere in your ~/.bashrc:
Cryo-EM reaches atomic resolution in protein structure determination
The end of the era of crystallography has been long predicted also on this blog, but has it come now with the recent report of an atomic resolution protein structure solved by cryo–electron microscopy (cryo-EM)?
Continue readingA new Graduate students (unexperienced) guide to academic literature.
Given this is my first ever attempt at a blog post, let alone one on such a highly regarded platform I feel it’s proper that I introduce myself. Hi, my name is Maranga, I am a second-year SABS student starting my DPhil project in Small molecules, and honestly, I really don’t like reading. Especially, scientific journals. Now I can appreciate this does not bode well given my chosen career path, however, my aversion for reading is not new (shoutout to Biff, Chip and Kipper) and hopefully not permanent.
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