Sagar Khare

Nature magazine asked me to write a "News& Views" article on a recent paper on computational enzyme design. We enjoyed writing it (especially for non-specialists), hope you enjoy reading it (and the excellent paper by Fleishman et al. it accompanies)!

Shared PDF link: rdcu.be/evlwJ
lnkd.in/eKxXm_b6

Inverse problems with experiment-guided AlphaFold Proteins exist as a dynamic ensemble of multiple conformations, and these motions are often crucial for their functions. However, current structure prediction methods predominantly yield a single conf...

📢 New preprint, lead by Alex Bronstein, @sankethvedula.bsky.social and colleagues:
Guiding AlphaFold with experimental data.

This approach generates conformational ensembles guided by NMR, X-ray (or whatever) data. I am thrilled to tackle lots of exciting problems with it!
arxiv.org/abs/2502.09372

Bluesky Chem Starter Packs

I wasn't expecting to reach a point where this list has 89 chemistry (loosely defined, by me, therefore likely inaccurate) starter packs.

tinyurl.com/ChemSkyStart...

It shows how many chemists have moved over to Bluesky! I wonder if this will reach 100? We might need to get more niche! 🥰

Synergistic Multi-Pronged Interactions Mediate the Effective Inhibition of Alpha-Synuclein Aggregation by the Chaperone HtrA1 The misfolding, aggregation, and the seeded spread of alpha synuclein (α-Syn) aggregates are linked to the pathogenesis of various neurodegenerative diseases, including Parkinson’s disease (PD). Under...

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

Great and long-time-in-the-making story!

So, how does the chaperone HtrA1 do it? Well, it uses cool tricks: it uses two (important) places to bind not one, it not just binds but also cuts its target, and it binds to various species (seeds, monomers) along the aggregation pathway. See how we figured it out! (4/n)

In the classical inhibition paradigm, a protein is inhibited by (think antibodies) by binding tightly at one site. This is quite challenging to do if you have, literally, a very moving target in the form of a disordered protein. Moreover, aggregation pathways involve species with >1 chains (3/n)

With this broader motivation and in collaboration with Jean Baum's group, we brought to bear a number of computational and experimental biophysical tools (including cool Atomic Force Microscopy in Liquids!) to figure out how HtrA1 inhibits the aggregation and prion-like spread of a-synuclein. (2/n)

New pre-print alert! How does a chaperone prevent protein aggregation, especially of intrinsically disordered proteins? If we learn how, perhaps we could design inhibitory proteins based on the same mechanistic blueprint as much-needed therapeutic leads against neurodegenerative diseases. (1/n)

Hello world! Feels good to be here :)