Author Archives: Dominik

The Smallest Allosteric System

Allostery is still a badly understood but very general mechanism in the protein world. In principle, an allosteric event occurs when a ligand (small or big) binds to a certain site of a protein and something (activity or function) changes at a different, distant site. A well-known example would be G-protein-coupled receptors that transport such an allosteric signal even across a membrane. But it does not have to be that far apart. As part of the Protein Folding and Dynamics series, I have recently watched a talk by Peter Hamm (Zurich) who presented work on an allosteric system that I thought was very interesting because it was small and most importantly, controllable.

PDZ domains are peptide-binding domains, often part of multi-domain proteins. For the work presented the researchers used the PDZ3 domain which is a bit special and has an additional (third) C-terminal α-helix (α3-helix) which is packing to the other side of the binding pocket. Previous work (Petit et al. 2009) had shown that removal of the α3-helix had changed ligand affinity but not PDZ structure, major changes were of an entropic nature instead. Peter Hamm’s group linked an azobenzene-derived photoswitch to that α3-helix; in its cis configuration stabilizing the α3-helix and destabilising in trans (see Figure 1).

Figure 1: PDZ3 domain (purple) and photoswitch (red) have different affinities for the peptide ligand (green), depending on the photoswitch’s isomerisation state (and temperature). From Bozovic, O., Jankovic, B. & Hamm, P. Sensing the allosteric force. Nat Commun 11, 5841 (2020). https://doi.org/10.1038/s41467-020-19689-7
Continue reading →

Climate Change @ ISMB

Another special session I was listening to at ISMB 2020 was the Green stream. Several talks dealt with climate change and its relation to bioinformatics and computational biology. Two of them I found particularly interesting, one calculating the carbon footprint of ISMB itself and the other calculating the footprint of specific bioinformatics tools.

I believe most people have realised how important the issue of human-made climate change is and I assume that everyone has heard about some aspects of our life that are causing particularly many emissions compared to certain alternatives. For example, train rides vs. short-haul flights, eating the food’s food (veggies) vs. mass production of meat or renewable energies vs. coal plants, just to name some that are rather easy to change. Admittedly, I have also underestimated the urgency of the issue and I found this plot quite convincing:

(Screenshot from Alex Bateman’s talk)

What can we as computational researchers do about it?

Continue reading →

Citizen Science in Video Games

What I really liked about visiting ISMB last year was their diversity of talks and subgroup meetings in all areas related to biology and computers. Last year I joined two talks about improving bioinformatics education which were really interesting because I hadn’t thought about that before. This year I joined a special session on citizen science.

Citizen science is public participation in scientific research and can be done by almost everyone. I had heard about Foldit or Rosetta@Home but (unfortunately) never participated. Those two projects deal with protein folding (how does a protein reach its final functional 3D structure?) which is an important scientific problem but is computationally very expensive to study. While one of the projects is a screensaver which uses free resources of personal computers, the other is a game where players can get highscores for folding protein fragments manually. Helping science in a playful way is cool by itself but the project that was presented in one of the talks brought this to the next level. A citizen science minigame was integrated into an action game for PCs and consoles.

Continue reading →

Using SLURM a little bit more efficiently

Your research group slurmified their servers? You basically have two options now.

Either you install all your necessary things on one of the slurm nodes within an interactive session, e.g.:

srun -p funkyserver-debug --pty --nodes=1 --ntasks-per-node=1 -t 00:10:00 --wait=0 /bin/bash

and always specify this node by adding the ‘#SBATCH –nodelist=funkyserver.cpu.do.work’ line to your sbatch scripts or you set up some template scripts that will help you to install all your requirements on multiple nodes so you can enjoy the benefits of the slurm system.

Here is how I did it; comments and suggestions welcome!

Step 1: Create an sbatch template file (e.g. sbatch_job_on_server.template_sh) on the submission node that does what you want. In the ‘#SBATCH –partition’ or ‘–nodelist’ lines use a placeholder, e.g. ‘<server>’, instead of funkyserver. 

For example, for installing the same conda environment on all nodes that you want to work on:

Continue reading →

Learning dynamical information from static protein and sequencing data

I would like to advertise the research from Pearce et al. (https://doi.org/10.1101/401067) whose talk I attended at ISMB 2019. The talk was titled ‘Learning dynamical information from static protein and sequencing data’. I got interested in it as my field of research is structural biology which deals with dynamics systems, e.g. proteins, but data is often static, e.g. structures from X-ray crystallography. They presented a general protocol to infer transition rates between states in a dynamical system that can be represented with an energy landscape.

Continue reading →

Journal Club: Investigating Allostery with a lot of Crystals

Keedy et al. 2018: An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering.

Allostery is defined as a conformational/activity change of an active site due to a binding event at a distant (allosteric) site.

The paper I presented in the journal club tried to decipher the underlying mechanics of allostery in PTP1B. It is a protein tyrosine phosphatase (the counter parts of kinases) and a validated drug target. Allosteric binding sites are known but so far neither active site nor allosteric site inhibitors have reached clinical use. Thus, an improved mechanistic understanding could improve drug discovery efforts.

Continue reading →