Malaria kills over 600,000 people annually. The parasite Plasmodium falciparum detoxifies hematin by forming hemozoin crystals—a validated drug target. Our research investigates how heme-artemisinin adducts inhibit hematin crystal growth, either reversibly or near-irreversibly, and how quinoline–artemisinin combinations can be optimized to restore sensitivity in drug-resistant parasites. Using atomic force microscopy, parasite culture assays in both sensitive and resistant strains, and mouse models, we pursue three aims: (1) determine inhibitory concentrations and mechanisms of heme-artemisinin adducts; (2) assess reversibility of crystal inhibition in vitro and in vivo; and (3) evaluate how drug combinations impact parasite killing and hematin crystallization. The goal is to develop safer, more effective antimalarial regimens that are harder for parasites to evade.

Alzheimer's disease is characterized by accumulation of amyloid-β (Aβ) fibrils and plaques in the brain. We hypothesize that fibrils generate neurotoxic oligomers and fragments via fragmentation and secondary nucleation. Our approach combines molecular dynamics simulations with in situ atomic force microscopy (AFM) and transmission electron microscopy (TEM) to monitor individual fibril elongation in real time. By examining fibril tips across different polymorphs, peptide sequences, and inhibitor candidates, we pursue three aims: (1) determine how fibril structure and peptide sequence govern incoming peptide dynamics at the fibril tip; (2) identify neurotoxic Aβ aggregates and elucidate their formation mechanisms; and (3) establish strategies to suppress or redirect fibril growth. This synergistic approach directly targets the most therapeutically relevant events in fibrillization while avoiding confounding bulk nucleation processes.

Mesoscopic protein-rich clusters—submicron assemblies with kinetically determined sizes and thermodynamically controlled populations—are critical precursors to crystallization, amyloid formation, and sickle hemoglobin polymerization. We study how structural flexibility governs cluster formation across proteins including p53 (mutated in ~50% of human cancers), hemoglobin A, and lysozyme. Intrinsically disordered proteins like p53 form clusters at low concentrations under crowded, cell-like conditions. These clusters can trap surrounding molecules, raising the barrier to aggregation and potentially giving cellular repair systems time to act. Crucially, p53 fibril nucleation proceeds not from individual molecules but from these dense pre-assembled clusters—a new biological pathway with implications for cancer and neurodegeneration.

We have established the mechanisms by which several classes of antimalarial drugs inhibit hematin crystallization. Evidence indicates that hemozoin crystals form within lipid-based organic sub-phases inside the parasite's digestive vacuole via a classical layer-by-layer mechanism: new crystal layers nucleate on existing ones and spread by addition of solute molecules. Quinoline-class drugs bind to specific crystal surface sites, blocking incorporation of soluble hematin and halting crystal growth. Understanding these surface-specific binding interactions enables rational design of inhibitors and informs combination drug strategies.

A single compound can crystallize into multiple distinct structures—polymorphs—with different solubility, compressibility, and bioavailability. Approximately 75% of compounds in the Cambridge Structural Database adopt more than one crystal form. Uncontrolled polymorphism has caused costly manufacturing failures, such as the ritonavir case in which a more stable, less soluble polymorph displaced the intended drug form. The free energy landscape of crystal polymorphs contains multiple local minima of similar energy, making prediction and control challenging. Our research integrates molecular modeling and analytical theory with thermodynamic measurements (enthalpies, entropies, free energies) and kinetic data (nucleation rates, precursor properties) to: (i) predict the number of accessible polymorphs a compound can form; (ii) understand their structural stability; and (iii) determine the sequence in which they appear. We then design and validate molecular template-based tools to nucleate desired forms or suppress unwanted ones.