Kresten Lindorff-Larsen

Determining accurate conformational ensembles of intrinsically disordered proteins at atomic resolution Nature Communications - This study demonstrates how to combine molecular dynamics computer simulations with experimental biophysical data to determine accurate atomic-resolution ensembles of...

Our work developing a maximum entropy reweighting method to refine all-atom ensembles of IDPs with extensive NMR and SAXS datasets is now out in @natcomms.nature.com:

rdcu.be/eKlK7

Led by @dartmouthchem.bsky.social graduate student Kaushilk Borthakur in collaboration with @bonomimax.bsky.social

This October I’m drawing one molecule a day inspired by proteins @rcsb.bsky.social

Day 1/31
Prompt MUSTACHE
Pdb 2QZI

Let’s start with something fun:
Mr. Potato head’s ‘stache is made of Androgen Receptor that binds testosterone and helps maintain his male phenotype

Next prompt: WEAVE
suggestions?

Prizes must recognize machine contributions to discovery The future of science will be written by humans and machines together. Awards should reflect that reality.

My HPLC was definitely overlooked

www.nature.com/articles/d41...

One of the great advantages of biology is that you can write HELLO WORLD in amino acids since PROTEINS ARE AMAZING

🧬 Use ESMFold Online | Neurosnap Bulk protein structure prediction model that only requires a single amino acid sequence as input. Much faster than AlphaFold2 since no MSAs are required (but slightly less accurate too).

I found out that Neurosnap offers ESMFold via API neurosnap.ai/service/ESMF...

I may test how many calls are possible with the free academic plan to see if it is worthwhile to update my repo.

Spread the word if you can.
We have an unused stopped flow accessory from Applied Photophysics. We traded in our Chirascan CD instrument so we have no use for this anymore. Reach out if you are interested and can find a home for this setup. Will ofcourse only work with a Chirascan!

In any case, I am happy that we were lucky enough to receive funding and am excited to be working on the project. To everyone else who have also been rejected multiple times, I wish you the best of luck—if you are lucky enough to be in a position where you can try again. 13/n; n=13

My impression as an ERC applicant, reviewer and panel member is that interdisciplinary science sometimes may have a hard time in the ERC system. But I also have seen that very field-specific proposals have fallen outside the expertise of the panels and reviewers. 12/n

While there are individual reviews I disagree with, I must say that through all of this I feel that the reviews have been fair and focused on the science of the proposals. The 2 CoG proposals received 7&10 set of reviews and the SyG proposal had 13 reviews. 11/n

Importantly, I’ve been lucky to have other sources of funding and so getting ERC funding was never a make-or-break situation for the group. I know this is not the case for everyone else. 10/n

In my case, it thus took four attempts to be funded by the ERC, and this involved three completely different projects and being pulled out of the reserve list. There’s no moral to this story, and I know others have been in the same or worse situations. 9/n

With DynaPLIX out of mind, I received an email in Dec 2022 saying that our “proposal has reached the stage of Grant Agreement preparation”. After a bit of confusion, we realized this might mean that our 2021 proposal had made it off the reserve list. 8/n

Based on the positive feedback from the 13 reviewers (!), we thus resubmitted DynaPLIX at the deadline in Nov 2022 which came only a few weeks after we got the reviews from the 2021 submission. 7/n

In 2021, we applied for ERC Synergy Grant with DynaPLIX and went through all three stages of the evaluation. We were ranked at 38%, below the 33% cutoff, but were put on the reserve list. 6/n

In 2017 I again applied for ERC CoG with a similar project (submitted to LS7 but moved by the ERC to LS1). Again, I went to step 2, but was ranked in the bottom 25% by LS1. 5/n

In 2016 I applied for an ERC Consolidator grant (PE4) for developing biophysical methods to understand and predict variant effects. The project went to the interview stage but wasn’t funded (ranking 41%; just below the 36% funding cutoff). 4/n

I first applied to the ERC for a Starting Grant in 2012 (LS1). The project, QBOND, aimed to improve our understanding and ability to model hydrogen bonds. The project (which I think was very exciting) got little love from the panel reviewers and didn’t make it past step 1. 3/n

A few years ago I received an ERC Synergy Grant. I realize that I am very fortunate and lucky to have received that grant, so wanted again to give a bit of background for the 10-year process it was for me to get funding from the ERC. This funding came in my fourth attempt. 2/n

Am at the University of Copenhagen Frontier Research in Denmark meeting celebrating the @erc.europa.eu. Rector David Lassen highlights how his first meeting with the ERC was a grant rejection, and how it's important to tell early career scientists about the CV of failure in addition to successes 1/n

This is reminiscent of the subset of bacterial toxins that hijack retrograde translocation and the ERAD machinery to get into the cytosol. Their active, translocated subunits are also lysine deserts!

Not to be confused with a lysine dessert (salty, bitter)
bsky.app/profile/lind...

Lysine deserts prevent adventitious ubiquitylation of ubiquitin-proteasome components - Cellular and Molecular Life Sciences In terms of its relative frequency, lysine is a common amino acid in the human proteome. However, by bioinformatics we find hundreds of proteins that contain long and evolutionarily conserved stretches completely devoid of lysine residues. These so-called lysine deserts show a high prevalence in intrinsically disordered proteins with known or predicted functions within the ubiquitin-proteasome system (UPS), including many E3 ubiquitin-protein ligases and UBL domain proteasome substrate shuttles, such as BAG6, RAD23A, UBQLN1 and UBQLN2. We show that introduction of lysine residues into the deserts leads to a striking increase in ubiquitylation of some of these proteins. In case of BAG6, we show that ubiquitylation is catalyzed by the E3 RNF126, while RAD23A is ubiquitylated by E6AP. Despite the elevated ubiquitylation, mutant RAD23A appears stable, but displays a partial loss of function phenotype in fission yeast. In case of UBQLN1 and BAG6, introducing lysine leads to a reduced abundance due to proteasomal degradation of the proteins. For UBQLN1 we show that arginine residues within the lysine depleted region are critical for its ability to form cytosolic speckles/inclusions. We propose that selective pressure to avoid lysine residues may be a common evolutionary mechanism to prevent unwarranted ubiquitylation and/or perhaps other lysine post-translational modifications. This may be particularly relevant for UPS components as they closely and frequently encounter the ubiquitylation machinery and are thus more susceptible to nonspecific ubiquitylation.

For our previous work on lysine deserts see

Kampmeyer et al, 2023:
Lysine deserts prevent adventitious ubiquitylation of ubiquitin-proteasome components
doi.org/10.1007/s000...

The proteasome-substrate-shuttle protein UBQLN2 contains—like other quality control system proteins—a long region devoid of lysine (a lysine desert)

Martin Grønbæk-Thygesen (from @rhp-lab.bsky.social) et al show that introducing K here causes ubiquitylation and degradation

doi.org/10.1101/2025...

A good day to remember John Gurdon’s school report from his biology master at Eton

🌟Om præcis et år i dag fylder Carlsbergfondet 150 år. Det fejrer vi med ekstraordinært at udbyde 150 mio kr til interdisciplinære forskningscentre, der skal fremme tværfagligheden i det danske grundforskningslandskab
👉 Læs om hvordan du kan søge bit.ly/42FWVv8 #dkforsk

And the legacy continues! 😊

@amjjbonvin.bsky.social @bioinfo.se @lindorfflarsen.bsky.social #EMBOIntegMod25 ! 🍀🧿

Check out our latest, where we investigate the molecular origin of differences between Lys and Arg and their roles in biomolecular #condensates

@dipcehu.bsky.social

www.biorxiv.org/content/10.1...

@amelierocks.bsky.social

Figure 1 from the review. Caption: Comparison of a schematic example showing static, time-dependent, and time-resolved experiments illustrated by a protein folding process. (a) A static experiment measuring the observable O$_{\text{exp}}$ is shown, which can be modelled as a distribution of simulated values, O$_{\text{calc}}$, representing a conformational ensemble of folded and unfolded states. (b) Shows a time-dependent experiment, where the equilibrium dynamics of reversible folding gives rise to measured transition times $\tau_1$ and $\tau_2$. These can be modelled as equilibrium dynamics, illustrated by a free energy (FE) surface along a chosen degree of freedom (D.O.F.) (c) A time-resolved experiment probes a non-equilibrium process, where the system begins at $t_{0}$ in the folded state. During the observation time $t$ the protein unfolds until $t_{\text{max}}$. At each time point, a distinct ensemble average, O$_{\text{exp}}$, can be observed, reflecting the proteins changing structure. This evolution can be modelled as distributions of O$_{\text{calc}}$ at each time point. These are shown together with a FE surface.

Integrative modelling of biomolecular dynamics

Time-dependent and -resolved experiments combined with computation provide a view on molecular dynamics beyond that available from static, ensemble-averaged experiments

Review w @dariagusew.bsky.social & Carl G Henning Hansen
doi.org/10.48550/arX...

Visiting Ephesus at #embointegmod25 to look for the missing AlphaFold 3 code