Multi-Scale Modeling of Soft Matter: Gas Vesicles and Red Blood Cells
Solares, Santiago D
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Modeling of soft matter, nowadays, became an extremely active research field due to the advancement in computational power and theoretical physics. Not only because we can access and study larger length scales and longer time scales, but also, the ability to model more complex systems. In this dissertation, we utilized the state-of-the-art computational and theoretical tools to model and study two systems. The first system is gas vesicles, a proteineous organelle that exist in microorganisms such as archea and bacteria. The structure and assembly process of gas vesicles have received significant attention in recent decades, although relatively little is still known. In this work we develop a model for the major gas vesicle protein, GvpA, and explore its structure within the assembled vesicle. Elucidating this protein's structure has been challenging due to its adherent and aggregative nature, which has so far precluded in-depth biochemical analyses. Moreover, GvpA has extremely low similarity with any known protein structure, which renders homology modeling methods ineffective. Thus, alternate approaches were used to model its tertiary structure. Starting with the sequence from haloarchaeon <italic>Halobacterium sp.NRC-1</italic>, we performed <italic>ab-initio</italic> modeling and threading to acquire a multitude of structure decoys, which were equilibrated and ranked using molecular dynamics and mechanics, respectively. The highest ranked predictions exhibited an $alpha;-$beta;-$beta;-$alpha; secondary structure in agreement with earlier experimental findings, as well as with our own secondary structure predictions. Afterwards, GvpA subunits were docked in a quasi-periodic arrangement to investigate the assembly of the vesicle wall and to conduct simulations of contact-mode atomic force microscopy imaging, which allowed us to reconcile the structure predictions with the available experimental data. Finally, the GvpA structure for two representative organisms, <italic>Anabaena flos-aquae</italic> and <italic>Calothrix sp. PCC 7601</italic>, was also predicted, which reproduced the major features of our GvpA model, supporting the expectation that homologous GvpA sequences synthesized by different organisms should exhibit similar structures. The second system studied in this dissertation is red blood cells and their hemolytic processes. Due to the significant progress that has been achieved in the treatment of patients with cardiovascular diseases, procedures such as heart valve replacements, either with mechanical or biological substitutes, have become routine operations. However, despite this progress, the use of cardiovascular implants always results in changes to the blood fluid dynamics, such that undesired damage to red blood cells (hemolysis) occurs. This type of damage, which can also be brought about by certain medical procedures, such as dialysis, reduces the ability of the circulatory system to transport oxygen and carbon dioxide. To gain a deeper understanding of the conditions leading to hemolysis and to aid in the design of low-hemolysis cardiovascular implants, this document proposes the development of a coarse-grained dynamics model to simulate red blood cells, which will be integrated into a computational fluid dynamics solver and packaged into an integrated software tool. A novel aspect of the proposed model will be its ability to reproduce interactions between different red blood cells in large scale simulations, as well as hemolysis at the single-cell level due to the stresses imparted by the fluid. The model will be validated against previous experiments reported in the literature and will also be used to simulate model biodevices.