Design spin cluster for NMR signal amplification and quantum resonance sensing
To reveal “invisible” NMR signal of surfaces, active sites, and functional species in catalysis, molecular recognition and quantum materials using out of the box tools.
Spying on Molecular Action with Spins
The Han lab pushes the frontier of magnetic resonance to discover new chemistry principles in water and through control over the shaping and ordering of dynamic water. We use advanced magnetic resonance manipulation and control over the spatial organization of electron and nuclear spin clusters located on biomolecular surface, soft materials or nanomaterials to uncover their structure, the design rules for molecular recognition, and the surface structuring and dynamics of hydration water.
The development effort requires multiple research tools in the realm of physical chemistry broadly speaking. They include instrument development to achieve hyperpolarization and quantum resonance sensing, the design of precisely tuned electron and nuclear spin clusters, spin physic theory and simulations, and the dynamics and thermodynamics of solvation science to control biomolecular activity and directed assembly.
The Han lab is pushing the frontier of electron and nuclear spin magnetic resonance instrumentation and concepts in dynamic nuclear polarization (DNP) amplified nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR). We are motivated by the power of “Seeing is Believing”. Visualizing molecular interactions and materials interfaces, previously “invisible”, can fundamentally transform our ability to discover solutions, and almost as importantly, ask new questions.
Areas Of Research
Research in the Han Lab builds and employs state-of-the-art tools in magnetic resonance spectroscopy to advance our understanding in different subject areas, ranging from quantum sensing, solvation science, biophysics to neurodegenerative diseases.
SEE ALL RESEARCH
Water directed protein assembly for shape control and templated self-replication
To understand, control and engineer protein aggregation pathways, protein surface activity to protein liquid-liquid phase separation.
Water as a shape-shifting and active biological building block
To reveal long-standing questions on the structure and dynamics of water on proteins, membranes to catalyst support surfaces.
Publications
+ VIEW ALL
Passaging Human Tauopathy Patient Samples in Cells Generates Heterogeneous Fibrils with a Subpopulation Adopting Disease Folds
, K., , , , , , , , ,
The discovery by cryo-electron microscopy (cryo-EM) that the neu-ropathological hallmarks of different tauopathies, including Alzheimer’s disease, corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), are caused by unique misfolded conformations of the protein tau is among the most profound developments in neurodegenerative disease research. To capitalize on these discoveries for therapeutic development, one must achieve in vitroreplication of tau fibrils that adopt the representative tauopathy disease folds, which represents a grand challenge for the field. A widely used approach has been seeded propagation using pathological tau fibrils derived from post-mortem patient samples in biosensor cells that expresses a fragment of the tau protein known as K18, or Tau4RD, containing the microtubule-binding repeat domain of tau as the substrate. The new insights from cryo-EM raised the question of whether the Tau4RD fragment is capable of adopting characteristic tau folds found in CBD and PSP patient fibrils, and whether cell-passaged and amplified tau fibrils can be used as seeds to achieve cell-free assembly of recombinant 4R tau into fibrils without the addition of cofactors. Using Double Electron Electron Resonance (DEER) spectroscopy, we discovered that cell-passaged pathological seeds generate heterogeneous fibrils that are, however, distinct between the CBD and PSP lysate-seeded fibrils, and vastly different from heparin-induced tau fibril structures. Moreover, the lysate-seeded fibrils contain a characteristic sub-population that resembles the disease fold corresponding to the respective starting patient sample. These findings indicate that templated propagation using CBD and PSP patient-derived fibrils is possible with a tau fragment that does not contain the entire pathological fibril core, but also that additional mechanisms must be tuned to converge on a homogeneous fibril population.
Localized Reconstruction of Multimodal Distance Distribution from DEER Data of Biopolymers
, , , , ,
Pulsed Dipolar ESR Spectroscopy (PDS) is a uniquely powerful technique to characterize the structural property of intrinsically disordered proteins (IDPs) and polymers and the conformational evolution of IDPs and polymers, e.g. during assembly, by offering the probability distribution of segment end-to-end distances. However, it is challenging to determine distance distribution P(r) of IDPs by PDS because of the uncertain and broad shape information that is intrinsic to the distance distribution of IDPs. We demonstrate here that the Srivastava-Freed Singular Value Decomposition (SF-SVD) point-wise mathematical inversion method along with wavelet denoising (WavPDS) can aid in obtaining reliable shapes for the distance distribution, P(r), for IDPs. We show that broad regions of P(r) as well as mixed narrow and broad features within the captured distance distribution range can be effectively resolved and differentiated without a priori knowledge. The advantage of SF-SVD and WavPDS is that the methods are transparent, requiring no adjustable parameters, the processing of the magnitude for the probability distribution is performed separately for each distance increment, and the outcome of the analysis is independent of the user’s judgement. We demonstrate the performance and present the application of WavPDS and SF-SVD on model ruler molecules, model polyethylene glycol polymers with end-to-end spin labeling, and IDPs with pairwise labeling spanning different segments of the protein tau to generate the transparent solutions to the P(r)’s including their uncertainties and error analysis.
Phosphoryl group wires stabilize pathological tau fibrils as revealed by multiple quantum spin counting NMR
, , , , , ,
Hyperphosphorylation of the protein tau is one of the biomarkers of neurodegenerative diseases in the category of tauopathies. However, the molecular level, mechanistic, role of this common post- translational modification (PTM) in enhancing or reducing the aggregation propensity of tau is unclear, especially considering that combinatorial phosphorylation of multiple sites can have complex, non-additive, effects on tau protein aggregation. Since tau proteins stack in register and parallel to elongate into pathological fibrils, phosphoryl groups from adjacent tau strands with 4.8 Å separation must find an energetically favorable spatial arrangement. At first glance, this appears to be an unfavorable configuration due to the proximity of negative charges between phosphate groups from adjacent neighboring tau fibrils. However, this study tests a counterhypothesis that phosphoryl groups within the fibril core-forming segments favorably assemble into highly ordered, hydrogen-bonded, one-dimensionally extended wires under biologically relevant conditions. We selected two phosphorylation sites associated with neurodegeneration, serine 305 (S305p) and tyrosine 310 (Y310p), on a model tau peptide jR2R3-P301L (tau295-313) spanning the R2/R3 splice junction of tau, that readily aggregate into a fibril with characteristics of a seed-competent mini prion. Using multiple quantum spin counting (MQ-SC) by 31P solid-state NMR of phosphorylated jR2R3-P301L tau peptide fibrils, enhanced by dynamic nuclear polarization, we find that at least six phosphorous spins must neatly arrange in 1D within fibrils or in 2D within a protofibril to yield the experimentally observed MQ-coherence orders of four. We found that S305pstabilizes the tau fibrils and leads to more seeding-competent fibrils compared to jR2R3 P301L or Y310p. This study introduces a new concept that phosphorylation of residues within a core forming tau segment can mechanically facilitate fibril registry and stability due a hitherto unrecognized role of phosphoryl groups to form highly ordered, extended, 1D wires that stabilize pathological tau fibrils.
Recent News
+ VIEW ALL
1st Han Lab Undergrad Research Slam!
February 13, 2025
We made dumplings to celebrate Lunar New Year!
February 7, 2025
Celebrating Songi’s Birthday!
January 8, 2025
Interested in joining the Han research group? Reach us at han-ofc@northwestern.edu
Follow us at @songihanlab