Early Onset of Kinetic Roughening due to a Finite Step Width in Hematin Crystallization

The structure of the interface of a growing crystal with its nutrient phase largely determines the growth dynamics. We demonstrate that hematin crystals, crucial for the survival of malaria parasites, transition from faceted to rough growth interfaces at increasing thermodynamic supersaturation Δμ. Contrary to theoretical predictions and previous observations, this transition occurs at moderate values of Δμ. Moreover, surface roughness varies nonmonotonically with Δμ, and the rate constant for rough growth is slower than that resulting from nucleation and spreading of layers. We attribute these unexpected behaviors to the dynamics of step growth dominated by surface diffusion and the loss of identity of nuclei separated by less than the step width w. We put forth a general criterion for the onset of kinetic roughening using w as a critical length scale.National Institutes of Health (U.S.) (Grant 1R21AI126215-01)National Science Foundation (U.S.) (Grant DMR-1710354)United States. National Aeronautics and Space Administration (Grant NNX14AD68G)United States. National Aeronautics and Space Administration (Grant NNX14AE79G)Robert A. Welch Foundation (Grant E-1794

Deciphering the Molecular Interactions Between Antimalarials and Hematin Crystal Surfaces

The unique physicochemical properties of crystals are essential for a variety of commercial applications, consumer products, and functional roles in diverse natural, synthetic, and biological systems. Facile methods of tailoring crystal properties, such as altering growth conditions, are characteristically inadequate and nontrivial. One versatile approach to control crystallization involves the use of modifiers, which are additives that interact with crystal surfaces to alter their growth rates. Elucidating their binding specificity is a ubiquitous challenge that is critical to their design as well as understanding their role in natural processes. In this dissertation project, we selected hematin, a pathological crystal that is relevant to malaria, as a model system to examine the complementarity of antimalarial drugs to crystal surfaces. Approximately 40% of the global population is at risk for malaria infection and 300 – 660 million clinical episodes of Plasmodium falciparum malaria occur annually. During the parasite lifecycle in human erythrocytes, heme released during hemoglobin catabolism is detoxified by sequestration into crystals. Many antimalarials are believed to suppress the parasite by inhibiting hematin crystallization. Despite significant advancement, fundamental questions regarding hematin growth and inhibition remain. We employ time-resolved in situ atomic force microscopy paralleled with bulk crystallization to show that the lipid sub-phase in the parasite may be a preferred growth environment. We present the first evidence of a molecular mechanisms of hematin crystallization and antimalarial drug action as crystal growth inhibitors. Our observations demonstrate that hematin crystals grow via a classical mechanism wherein layers are generated by two-dimensional nucleation and spread. Four classes of surface sites are identified for binding of potential drugs and could advance future design and/or optimization of new antimalarials. We provide evidence that antimalarials suppress crystal growth by binding directly to surfaces. We elucidate how subtle rearrangement and removal of functional moieties on quinoline isomers and analogues can create effective or ineffective modifiers, along with tuning their inhibitory modes of action. These findings enable the identification and optimization of chemical moieties that bind to surface sites, thus providing guidelines for the discovery of antimalarials to combat parasite resistance. Our findings highlight the importance of specific functional moieties in quinoline-class compounds, leading to an improved understanding of modifier – crystal interactions that could prove to be broadly applicable to the design of new generation antimalarial drugs to combat the increased resistance of malaria parasites to existing therapies.Chemical and Biomolecular Engineering, Department o

Advances in Biomaterials for Drug Delivery

Advances in biomaterials for drug delivery are enabling significant progress in biology and medicine. Multidisciplinary collaborations between physical scientists, engineers, biologists, and clinicians generate innovative strategies and materials to treat a range of diseases. Specifically, recent advances include major breakthroughs in materials for cancer immunotherapy, autoimmune diseases, and genome editing. Here, strategies for the design and implementation of biomaterials for drug delivery are reviewed. A brief history of the biomaterials field is first established, and then commentary on RNA delivery, responsive materials development, and immunomodulation are provided. Current challenges associated with these areas as well as opportunities to address long-standing problems in biology and medicine are discussed throughout.National Institutes of Health (Award CA200351)Burroughs Wellcome Fund (Grant 1015145

Confined Dynamics of Grafted Polymer Chains in Solutions of Linear Polymer

We measure the dynamics of high molecular weight polystyrene grafted to silica nanoparticles dispersed in semidilute solutions of linear polymer. Structurally, the linear free chains do not penetrate the grafted corona but increase the osmotic pressure of the solution, collapsing the grafted polymer and leading to eventual aggregation of the grafted particles at high matrix concentrations. Dynamically, the relaxations of the grafted polymer are controlled by the solvent viscosity according to the Zimm model on short time scales. On longer time scales, the grafted chains are confined by neighboring grafted chains, preventing full relaxation over the experimental time scale. Adding free linear polymer to the solution does not affect the initial Zimm relaxations of the grafted polymer but does increase the confinement of the grafted chains. Our results elucidate the physics underlying the slow relaxations of grafted polymer