Thanks to @snsf.ch, we are hiring two PhD students to investigate frontier topics in lipid biology using a combination of MD simulations and experiments. Preferred starting date: ASAP. Fribourg - and Switzerland - are quite nice, for both work and private life! Please spread the word!

Happy to share the latest from the lab, led by Daniel Alvarez, in collaboration with @lizconibear.bsky.social‬. In this AA-MD tour-de-force, we delve deep into the mechanism and energetics of lipid uptake by bridge-like lipid transfer proteins, and we learn a few interesting things along the way...

We also modelled Brl1 in curved membranes (a vesicle mimicking the INM shape). Same result: Brl1/Brr6 oligomers stably interacting and promoting lipid mixing within the channel. (11/13)

When observed closely, lipid mixing looks like classic hemifusion-like intermediates with exposed lipid-tails (but stabilized within protein rings here). (10/13)

But here is another interesting part: interaction between Brl1 and Brr6 only happens when the membranes are < 10 nm apart. This is also very consistent with previous measurement of these distances in NPC assembly intermediates prior to fusion. (9/13)

We went back to simulations of opposed bilayers, but with protein oligomers in both of them. We observed a gradual decrease in membrane distances to the point of interaction between proteins (Brl1 and Brr6). This interaction results in lipid mixing in the central channel of the rings. (8/13)

Given that both Brl1 and Brr6 are essential, and their interaction has been studied in earlier work, we modeled 16 copies of Brl1 together with 16 of Brr6. We got a 32-mer complex with two subunits of 16-mers of Brl1/Brr6 with a head-to-head interaction mediated by a hydrophobic loop motif. (6/13)

Our MD simulations of ring oligomers of Brl1/Brr6 showed pronounced lipid-remodeling in its vicinity. Could this lipid remodeling be enough to drive fusion of INM-ONM? The answer is NO, based on simulation of two opposed bilayers, with protein in only one of them. (5/13)

AF3 led us to find that both Brl1 and Brr6 tend to self-associate and form multimeric structures that become fully closed rings when 10 or more copies are present. By mutating charged residues at the dimer interface, we showed that this side-by-side oligomerization is critical. (4/13)

We found that Brl1 localizes to NPC assembly sites via an N-terminal nuclear export signal (NES). At that site, Brl1 and Brr6 oligomerize into rings, bridging membranes by interacting through conserved hydrophobic loops, promoting lipid mixing. Continue for more details! (3/13)

Meet Brl1 and Brr6: two highly conserved transmembrane proteins in yeast, localized to the inner (INM) and outer nuclear membranes (ONM), respectively. Both are essential for NPC assembly, and despite their similarity, they are non-redundant. (2/13)

Happy to share the latest work from the lab, led by @mudgal17.bsky.social‬, in collaboration with the Weis lab @ethzurich.bsky.social.
How do nuclear membranes fuse during NPC assembly? We answer this question in our latest work, where we identify a new mechanism for membrane fusion… (1/13)

Our lab is hiring 1 PhD and 1 Postdoc to study the mechanism of lipid transport using computational methods (Molecular Dynamics, AI). Fully funded by @snsf-ch.bsky.social for 4 years, with amazing collaborators and excellent life and working conditions. Apply by email. Please share and repost!

Join us in Heidelberg! Registration closes in 5 days!