Excited to share a preprint of: "Monomer binding modes of small molecules that modulate the kinetics of hIAPP amyloid formation" The first paper from @DartmouthChem PhD student (and fellow @pomonacollege sagehen alum!) Michelle Garcia together with post-doc Korey Reid.

Fun day at @DartmouthChem serving buldak ramen and explaining the biophysics and structural biology of heat and capsaicin activation of the ion channels for @AmerChemSociety National Chemistry Week!

Take note of our 15 (!) exp. refined IDP ensembles deposited in the @proteinEnsemble (example: https://t.co/SnVmFa1Mi4) If you think you have good method / force field for generating IDP ensembles - you can benchmark your agreement with exp data against these ensembles.

Paper: https://t.co/MoeiyD2aFp Code: https://t.co/ZJ77fyP7U3

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 Led by @DartmouthChem graduate students Kaushilk Borthakur and Thomas Sisk in collaboration with @BonomiMax .

Ensembles + Code: https://t.co/V4HECum55C Paper:

Here's a thread describing the results. https://t.co/53acfI0h2J

Check out our new preprint characterizing the binding mechanisms of small molecules that inhibit or accelerate the aggregation of human islet amyloid polypeptide, which is associated with type II diabettes.

...we're super excited to use MD simulations to study how these ligands affect the process of oligomerization of hIAPP and start trying to design more potent aggregation inhibitors. The GPUs are already churning! Congrats to Michelle and Korey on their beautiful work!

These simulations gives us a mechanistic framework to begin to understand the structure-activity-relationship of ligands that inhibit or accelerate the aggregation of hIAPP. New @RadfordLab work ( https://t.co/x1GlZas4xO) gives us new ligands to look at and...

While they're only rarely populated at the same time - these multisite binding mode give us a better understanding of how a network of hydrogen bond donors and acceptors confer pronounced affinity to residues 7_CATQRLANFLV_17.

To get more insight into the diversity of binding modes and search for more structured modes - we looked at binding poses where at least 15 residues of hIAPP were in contact with each ligand. This represented 12.9% of bound frames for YX-I-1 but only 3.9% of YX-A-1.

Interestingly, the exposed regions of YX-A-1 are quite hydrophobic (cylcohexane and benzene) - and we think this could be part of how it accelerates aggregation into higher order oligomers and protofilaments

We see that each ligand has moieties that are consistently buried and others that are consistently exposed across binding modes. We think that buried moieties might confer monomer affinity - while exposed moieties could affect rates of oligomerization into higher order species.

Comparing populations of intermolecular interactions we found something unique about this pair: the largest difference is elevated populations of hydrogen bonds with YX-I-1, not increased populations of aromatic stacking interactions -which we usually see in tighter IDP ligands

We have a detailed comparison of contact profiles and helicity changes with NMR CSPs from in the SI. We don't see perfect agreement, but observe that the average magnitude of CSPs correlate pretty well with average contact populations and changes in helicity upon and binding.

In ligand binding simulations, we see heterogenous ensembles of binding modes. We see YX-I-1 is a tighter binder than YX-A-1, and produces larger conformational changes upon binding, consistent with larger NMR chemical shift perturbations (CSPs) from the @RadfordLab.

Michelle had an awesome idea to use matrices of circuit topology assignments from work by @AlirezaMashaghi ( https://t.co/t0UtdvpXea) for dimensionality reduction to project all our apo and holo ensembles onto latent space reflecting the topological similarity of conformations.

Our WT hIAPP ensemble is in good agreement with NMR chemical shifts, showing us we have a good force field (a99SB-disp) for this system. S20G introduces a central hinge that increases populations of intramolecular contact and beta-sheets bewteen residues in hIAPP fibril cores

We used 400us of enhanced sampling (REST2) all-atom MD to characterize the conformational ensembles of wild-type (WT) hIAPP, and the S20G variant (which accelerates aggregation and is associated with early-onset T2D) and characterize their interactions with these ligands.

Recently, the @RadfordLab ran a screen of 1500 small molecules to find hIAPP binders ( https://t.co/y5qo0pz10G) and found small molecules that inhibit (YX-I-1) and accelerates (YX-A-1) hIAPP aggregation. YX-I-1 could be a lead for developing T2D therapies.