Faculty Directory

• Neurodegenerative diseases – Parkinson’s Disease
  Investigating the molecular underpinnings of Parkinson’s, including protein aggregation, mitochondrial dysfunction, and neuroinflammation, using integrative structural and cellular biology approaches.

• Cancer biology and targeted therapies
  Studying aberrant signaling pathways and protein complexes in cancer, with a focus on exploiting structural vulnerabilities for therapeutic development.

• Compartmentalization in cellular systems (e.g., cancer and neurodegeneration)
  Exploring how cells use spatial organization—through organelles, protein scaffolds, and membraneless compartments—to regulate complex processes in disease contexts.

p53, Cancer and Chemoresistance

At the Sinha Lab, we’re obsessed with the misbehaving molecules that drive disease. Our main character? p53, the so-called “guardian of the genome”—until it mutates and turns rogue in cancer. We focus on a hotspot: the R273 mutation. But here’s the catch—not all R273 mutants act the same. [R273H] stays relatively stable, [R273C] forms neat amyloid clumps via disulfide bonds, and [R273L]? It’s the wild one, aggregating through hydrophobic chaos. Using biophysics, simulations, and imaging, we’ve decoded how these mutants destabilize, misfold, and contribute to different cancer outcomes.

But it doesn’t stop there. Even wild-type p53 isn’t off the hook. When exposed to doxorubicin—a common chemo drug—it starts co-assembling into droplets via liquid-liquid phase separation. Some mutants don’t even need the drug to phase separate—they do it all on their own. [R273C] stays fluid; [R273L] goes solid. These phase transitions could be the missing link to understanding chemo resistance and cancer relapse.

From cancer to condensation, our work lives at the edge of protein chaos.  [Colloids and Surfaces B: Biointerfaces 212, 112371; Biophysical journal 118 (3), 720-728]

Packing Proteins with Purpose: The Microcompartment Chronicles

At the Sinha Lab, we decode how bacteria build their protein-based nanofactories—bacterial microcompartments (MCPs). Studying the pdu operon, we found that gene order isn’t about sequence similarity but how strongly the proteins interact—genome layout tuned for efficient assembly. We showed that Pdu shell proteins self-assemble via phase separation, forming enzyme-loaded droplets that boost catalytic activity. These shell proteins also moonlight as bioelectronic materials, generating photocurrent under UV light and revealing a proton-coupled electron transfer mechanism enhanced by genetic tweaks. From operon logic to light-harvesting protein pods, we’re revealing how nature builds and powers its own molecular machines. [BBA-General Subjects 1869 (6), 130794; bioRxiv, 2024.12. 16.628711; Journal of Materials Chemistry. B, 4842-4854; Biochemical Journal 480 (8), 539-553]

Role of Bile Acids and Doxorubicin in Parkinson's Disease

At the Sinha Lab, we’re on a mission to crack the molecular mysteries behind Parkinson’s disease (PD)—and our suspect list goes beyond the brain. It turns out the gut and cancer drugs might be stirring the pot. We've discovered that bile acids, like lithocholic acid (LCA) and deoxycholic acid (DCA)—usually busy helping digestion—are also busy hijacking α-synuclein. LCA binds to its sticky NAC region and slashes the aggregation lag time by 75%, forming SDS-resistant, toxic oligomers. DCA’s a bit gentler but still speeds things up. And when LCA and DCA join forces? It’s a molecular mess—more tangles, more toxicity. This gut-brain link might be a key player in PD pathogenesis.

But the surprises don’t stop there. Our lab also found that doxorubicin, a widely used chemotherapy drug, interacts with α-synuclein and destabilizes its structure, leading to aggregation—a possible explanation for Parkinson’s-like symptoms in some cancer patients. Interestingly, when L-DOPA, the gold-standard PD medication, enters the scene, it puts the brakes on aggregation. This points toward a new layer of neuroprotection—not just through dopamine, but by directly interfering with protein misfolding.

From bile acids to chemo cocktails, we're decoding how external triggers push α-synuclein over the edge—and how we might pull it back. If you’re curious about how gut chemistry, drugs, and rogue proteins collide, you’ll feel right at home here.[Current Research in Structural Biology 7, 100133; ACS Chemical Neuroscience 15 (21), 4055-4065]

Catalysis in a Droplet

At the Sinha Lab, we’re giving catalysis a new home: inside liquid droplets. No walls, no barriers—just phase-separated goo that turbocharges chemical reactions. Our experiments show that liquid–liquid phase separation (LLPS) can boost metal nanocatalyst activity by nearly 10x, all without needing fancy protein folding or rigid enclosures. Think of it as nature’s soft reactor—wet, wiggly, and wildly efficient.

But it’s not all fast lanes. We found that when the substrate concentration gets too high, the droplet interior shifts—slowing things down instead of speeding them up. These substrate-induced phase transitions jam molecular traffic inside the droplet, reducing the movement of both reactants and products—and surprisingly, this bottleneck lowers the reaction rate. It’s a twist no one saw coming.

So whether droplets act like boosters or bottlenecks depends on just the right molecular crowd. We're now decoding how squishy confinement rewires chemistry—opening up new routes in nanocatalysis, synthetic biology, and even smart drug delivery. [Chem. Commun., 2022,58, 8634-8637; Nanoscale 16 (31), 14730-14733]