Paul Robustelli
@paulrobustelli.bsky.social
Assistant Professor at Dartmouth College
Computational Biophysics / Disordered Proteins / Molecular Recognition
Computational Biophysics / Disordered Proteins / Molecular Recognition
Also, take note of our 15 (!) exp. refined all-atom IDP ensembles deposited in the protein ensemble database:
proteinensemble.org/entries/PED0...
If you think you have good method / force field for generating IDP ensembles, you can benchmark your agreement with exp. against these ensembles.
proteinensemble.org/entries/PED0...
If you think you have good method / force field for generating IDP ensembles, you can benchmark your agreement with exp. against these ensembles.
October 10, 2025 at 3:47 PM
Also, take note of our 15 (!) exp. refined all-atom IDP ensembles deposited in the protein ensemble database:
proteinensemble.org/entries/PED0...
If you think you have good method / force field for generating IDP ensembles, you can benchmark your agreement with exp. against these ensembles.
proteinensemble.org/entries/PED0...
If you think you have good method / force field for generating IDP ensembles, you can benchmark your agreement with exp. against these ensembles.
Code is here: github.com/paulrobustel...
GitHub - paulrobustelli/Borthakur_MaxEnt_IDPs_2024: Code Accompanying "Towards accurate, force field independent conformational ensembles of intrinsically disordered proteins" by Borkthakur et al.
Code Accompanying "Towards accurate, force field independent conformational ensembles of intrinsically disordered proteins" by Borkthakur et al. - GitHub - paulrobustelli/Borthakur_MaxE...
github.com
October 10, 2025 at 3:33 PM
Code is here: github.com/paulrobustel...
Congrats to Michelle and Korey on their beautiful work!
Paper:
www.biorxiv.org/content/10.1...
Ensembles, Simulation Inputs + Code: github.com/paulrobustel...
Paper:
www.biorxiv.org/content/10.1...
Ensembles, Simulation Inputs + Code: github.com/paulrobustel...
Monomer binding modes of small molecules that modulate the kinetics of hIAPP amyloid formation
Human islet amyloid polypeptide (hIAPP) forms amyloid fibrils that accumulate in pancreatic β-cells of Type II Diabetes (T2D) patients. Recently discovered small molecules that modulate the kinetics o...
www.biorxiv.org
September 27, 2025 at 1:45 PM
Congrats to Michelle and Korey on their beautiful work!
Paper:
www.biorxiv.org/content/10.1...
Ensembles, Simulation Inputs + Code: github.com/paulrobustel...
Paper:
www.biorxiv.org/content/10.1...
Ensembles, Simulation Inputs + Code: github.com/paulrobustel...
...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!
September 27, 2025 at 1:45 PM
...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!
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 @radford-lab.bsky.social work (pubs.acs.org/doi/full/10....) gives us new ligands to look at and...
Kinetic Steering of Amyloid Formation and Polymorphism by Canagliflozin, a Type-2 Diabetes Drug
Amyloid formation is involved in widespread health conditions such as Alzheimer’s disease, Parkinson’s disease, and type-2 diabetes. Amyloid fibrils have a similar cross-β architecture, but fibrils fo...
pubs.acs.org
September 27, 2025 at 1:45 PM
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 @radford-lab.bsky.social work (pubs.acs.org/doi/full/10....) 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.
September 27, 2025 at 1:45 PM
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.
September 27, 2025 at 1:45 PM
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
September 27, 2025 at 1:45 PM
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.
September 27, 2025 at 1:45 PM
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
September 27, 2025 at 1:45 PM
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.
September 27, 2025 at 1:45 PM
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) and other assays from @radford-lab.bsky.social
September 27, 2025 at 1:45 PM
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) and other assays from @radford-lab.bsky.social
Michelle had an awesome idea to use matrices of circuit topology assignments from work by @alirezamashaghi.bsky.social (pubs.acs.org/doi/full/10....) for dimensionality reduction to project all our apo and holo ensembles onto latent space reflecting the topological similarity of conformations.
September 27, 2025 at 1:45 PM
Michelle had an awesome idea to use matrices of circuit topology assignments from work by @alirezamashaghi.bsky.social (pubs.acs.org/doi/full/10....) 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
September 27, 2025 at 1:45 PM
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.
September 27, 2025 at 1:45 PM
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.
They found molecules that inhibit (YX-I-1) and accelerate (YX-A-1) hIAPP aggregation.
YX-I-1, which was found to bind monomer by NMR, SPR, and mass-spec could be a lead for developing T2D therapies. Kinetics assays show YX-A-1 mainly interacts with higher order oligomers.
YX-I-1, which was found to bind monomer by NMR, SPR, and mass-spec could be a lead for developing T2D therapies. Kinetics assays show YX-A-1 mainly interacts with higher order oligomers.
September 27, 2025 at 1:45 PM
They found molecules that inhibit (YX-I-1) and accelerate (YX-A-1) hIAPP aggregation.
YX-I-1, which was found to bind monomer by NMR, SPR, and mass-spec could be a lead for developing T2D therapies. Kinetics assays show YX-A-1 mainly interacts with higher order oligomers.
YX-I-1, which was found to bind monomer by NMR, SPR, and mass-spec could be a lead for developing T2D therapies. Kinetics assays show YX-A-1 mainly interacts with higher order oligomers.
Aggregation and amyloid formation of the disordered protein human islet amyloid polypeptide (hIAPP) is associated with type-2-diabetes (T2D).
Recently, @radford-lab.bsky.social ran a screen of 1500 small molecules to find hIAPP binders.
nature.com/articles/s41...
Recently, @radford-lab.bsky.social ran a screen of 1500 small molecules to find hIAPP binders.
nature.com/articles/s41...
September 27, 2025 at 1:45 PM
Aggregation and amyloid formation of the disordered protein human islet amyloid polypeptide (hIAPP) is associated with type-2-diabetes (T2D).
Recently, @radford-lab.bsky.social ran a screen of 1500 small molecules to find hIAPP binders.
nature.com/articles/s41...
Recently, @radford-lab.bsky.social ran a screen of 1500 small molecules to find hIAPP binders.
nature.com/articles/s41...