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<p dir="ltr">In life sciences, the determination of macromolecular structures and their functions, particularly proteins and protein complexes, is of paramount importance, as these molecules play critical roles within cells. The specific physical interactions of macromolecules govern molecular and cellular functions, making the 3D structure elucidation of these entities essential for comprehending the mechanisms underlying life processes, diseases, and drug discovery. Cryo-electron microscopy (cryo-EM) has emerged as a promising experimental technique for obtaining 3D macromolecular structures. In the course of my research, I proposed CryoREAD, an innovative AI-based method for <i>de nov</i>o DNA/RNA structure modeling. This novel approach represents the first fully automated solution for DNA/RNA structure modeling from cryo-EM maps at near-atomic resolution. However, as the resolution decreases, structure modeling becomes significantly more challenging. To address this challenge, I introduced Emap2sec+, a 3D deep convolutional neural network designed to identify protein secondary structures, RNA, and DNA information from cryo-EM maps at intermediate resolutions ranging from 5-10 Å. Additionally, I presented Alpha-EM-Multimer, a groundbreaking method for automatically building full protein complexes from cryo-EM maps at intermediate resolution. Alpha-EM-Multimer employs a diffusion model to trace the protein backbone and subsequently fits the AlphaFold predicted single-chain structure to construct the complete protein complex. Notably, this method stands as the first to enable the modeling of protein complexes with more than 10,000 residues for cryo-EM maps at intermediate resolution, achieving an average TM-Score of predicted protein complexes above 0.8, which closely approximates the native structure. Furthermore, I addressed the recognition of local structural errors in predicted and experimental protein structures by proposing DAQ, an evaluation approach for experimental protein structure quality that utilizes detection probabilities derived from cryo-EM maps via a pretrained multi-task neural network. In the pursuit of evaluating protein complexes generated through computational methods, I developed GNN-DOVE and DOVE, leveraging convolutional neural networks and graph neural networks to assess the accuracy of predicted protein complex structures. These advancements in cryo-EM-based structural modeling and evaluation methodologies hold significant promise for advancing our understanding of complex macromolecular systems and their biological implications.</p>

<p>  </p> <p>The investigation of laser-matter interactions has gained interest over the years due to the importance of these interactions in materials synthesis, diagnostics, electronics, and photonics. In-situ transmission electron microscopy (TEM) techniques are invaluable for real-time monitoring of dynamic processes in these systems at the nanoscale. In this work, the effect of pulsed laser heating on the reactions of energetic materials, plasmonic structures, and multilayer thin films has been studied by utilizing ultrafast transmission electron microscopy (UTEM) techniques. Heat transfer and electric field calculations have been carried out to compare and support the experimental findings. </p> <p>The photothermal reaction of an aluminum-fluoropolymer composite is studied to show the effect of pulsed laser heating on reactions of reactive materials. An aluminum nanoparticle - THV (terpolymer of tetrafluoroethylene, hexafluoropropylene, and vinylidene fluoride) sample is subjected to rapid heating and cooling cycles by employing the integrated laser system of an UTEM. TEM images and real-time movies (30 frame/s) are acquired to reveal the changes during the reaction. Heat transfer simulations proved that the temperature of the sample was high enough to trigger the decomposition of THV and start its reaction with Al nanoparticles. Electron diffraction patterns revealed that the reaction product was the rare and metastable η-phase aluminum fluoride (AlF3). The experimental and theoretical results showed that rapid pulsed laser heating and subsequent cooling of a nanoscale sample influences the phases that can form and be utilized to investigate other systems.</p> <p>Pulsed laser-assisted merging and alloying of noble metals are also studied to explore the fabrication of beaded gold-silver nanowires with a variety of morphology and composition. In-situ laser heating of plasmonic silver nanowire (Ag NW) - gold nanoparticle (Au NP) couples are performed inside an UTEM, and direct visualization of the evolution process gives insights into the formation mechanism. Experimental results show that silver melts at the surface to bridge the nanometer-sized gap between the NP and the NW, forming a cup-like morphology underneath the Au NP via capillary action. Progressive laser irradiation leads to wetting of the Au NP and the formation of a valley in the Ag NW around the NP, which flattens gradually by partial embedding of the NP. Inter-diffusion of Au into Ag and vice versa sets in at this stage, leading to depletion of Au from the Au-rich NP region. Prolonged irradiation and heating lead to gradual inter-mixing of Au-Ag, forming a beaded Au-doped Ag nanowire with homogeneous composition. Such a step-by-step understanding of the merging and alloying process has implications in nanowelding, which holds a future in designing efficient, transparent conductors and printed electronics. Numerical simulations are performed to calculate the electromagnetic enhancement at the interface of adjacent NPs and NWs and provide information on heat generation rates in NP-NW couples at the early stages of the nanowelding process. </p> <p>In the third chapter, laser-induced irreversible dynamics in electron beam sensitive organic energetic crystals and ultrathin multilayer films are studied by single-shot UTEM imaging. After various sample preparation methods are developed and compared for the well-controlled synthesis of nanoscale ammonium perchlorate samples on TEM grids, decomposition dynamics of ammonium perchlorate crystals are captured via single-shot imaging. The experimental data showed that the sublimation and decomposition are visible ~30 ns after the sample excitation laser in crystals smaller than 5 µm. Dependency of decomposition to crystal porosity and thickness is also observed with crack formation in some cases. In the following section, pulsed-laser irradiation is utilized to realize deformation in thin multilayer films under high temperatures, and triggered dynamic processes are investigated through single-shot imaging. Laser-assisted periodic wrinkle formation is demonstrated on SiN membranes coated with Ti/Ni bilayers. The resulting structures showed periodic wrinkling of the SiN membrane and corrugated surface formation on both sides of the film. Overall, the dissertation highlights the potential of ultrafast transmission electron microscopy in discovering fundamental processes related to, but not limited to, reactive materials, plasmonic nanomaterials, and ultrathin multilayer films. </p>