25 research outputs found
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Molecular and Stochastic Biophysical Modeling of mRNA Export and Quality Control
Molecular systems orchestrating the biology of the cell typically involve a complex web of interactions among various components and span a vast range of spatial and temporal scales. Export and quality control of messenger ribonucleic acids (mRNAs) feature a prominent example of such an intricate molecular system. Export of mRNAs into the cytoplasm is a fundamental step in gene regulation processes, which is meticulously quality controlled by highly efficient mechanisms in eukaryotic cells. Despite extensive research on how mRNAs are quality controlled prior to export into the cytoplasm, the exact underlying mechanisms are still under debate. Specifically, it is unclear how aberrant mRNAs are recognized and retained inside the nucleus. Computational methods have advanced our understanding of the behavior of molecular systems by enabling us to test assumptions and hypotheses, explore the effect of different parameters on the outcome, and eventually guide experiments. In this dissertation, I present my research on mRNA quality control using different computational techniques.Using the agent-based modeling (ABM) approach, which is an emerging molecular systems biology technique for exploring the dynamics of molecular systems/pathways in health and disease, we first developed a minimal model of the mRNA quality control (QC) mechanism. Our results suggested that regulation of the affinity of RNA-binding proteins (RBPs) to export receptors along with the weak interaction between the RBPs and nuclear basket proteins, namely myosin-like protein-1 (Mlp1) or translocated promoter region (Tpr) protein, are the minimum requirements to distinguish and retain aberrant mRNAs. In addition, we demonstrated how the length of mRNA may affect the QC process.The interaction between Mlp1 with one of the Saccharomyces cerevisiae RBPs, namely the nuclear polyadenylated RNA-binding protein (Nab2), was then investigated. Mlp1 plays a substantial role in mRNA quality control by interacting with other proteins involved in this process, specifically the RBPs. Yet, the mechanism of the interaction between Mlp1 and RBPs is still elusive. Using an array of integrated computational approaches including protein structure prediction, protein-protein docking, and molecular dynamics simulations, we dissected Mlp1-Nab2 interaction. Our results were consistent with experimental observations, which suggested that Nab2 residue F73 is essential for Mlp1 binding and further uncovered an indirect role of Nab2-F73 in this interaction
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Molecular and Stochastic Biophysical Modeling of mRNA Export and Quality Control
Molecular systems orchestrating the biology of the cell typically involve a complex web of interactions among various components and span a vast range of spatial and temporal scales. Export and quality control of messenger ribonucleic acids (mRNAs) feature a prominent example of such an intricate molecular system. Export of mRNAs into the cytoplasm is a fundamental step in gene regulation processes, which is meticulously quality controlled by highly efficient mechanisms in eukaryotic cells. Despite extensive research on how mRNAs are quality controlled prior to export into the cytoplasm, the exact underlying mechanisms are still under debate. Specifically, it is unclear how aberrant mRNAs are recognized and retained inside the nucleus. Computational methods have advanced our understanding of the behavior of molecular systems by enabling us to test assumptions and hypotheses, explore the effect of different parameters on the outcome, and eventually guide experiments. In this dissertation, I present my research on mRNA quality control using different computational techniques.Using the agent-based modeling (ABM) approach, which is an emerging molecular systems biology technique for exploring the dynamics of molecular systems/pathways in health and disease, we first developed a minimal model of the mRNA quality control (QC) mechanism. Our results suggested that regulation of the affinity of RNA-binding proteins (RBPs) to export receptors along with the weak interaction between the RBPs and nuclear basket proteins, namely myosin-like protein-1 (Mlp1) or translocated promoter region (Tpr) protein, are the minimum requirements to distinguish and retain aberrant mRNAs. In addition, we demonstrated how the length of mRNA may affect the QC process.The interaction between Mlp1 with one of the Saccharomyces cerevisiae RBPs, namely the nuclear polyadenylated RNA-binding protein (Nab2), was then investigated. Mlp1 plays a substantial role in mRNA quality control by interacting with other proteins involved in this process, specifically the RBPs. Yet, the mechanism of the interaction between Mlp1 and RBPs is still elusive. Using an array of integrated computational approaches including protein structure prediction, protein-protein docking, and molecular dynamics simulations, we dissected Mlp1-Nab2 interaction. Our results were consistent with experimental observations, which suggested that Nab2 residue F73 is essential for Mlp1 binding and further uncovered an indirect role of Nab2-F73 in this interaction
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Agent-Based Modeling in Molecular Systems Biology.
Molecular systems orchestrating the biology of the cell typically involve a complex web of interactions among various components and span a vast range of spatial and temporal scales. Computational methods have advanced our understanding of the behavior of molecular systems by enabling us to test assumptions and hypotheses, explore the effect of different parameters on the outcome, and eventually guide experiments. While several different mathematical and computational methods are developed to study molecular systems at different spatiotemporal scales, there is still a need for methods that bridge the gap between spatially-detailed and computationally-efficient approaches. In this review, we summarize the capabilities of agent-based modeling (ABM) as an emerging molecular systems biology technique that provides researchers with a new tool in exploring the dynamics of molecular systems/pathways in health and disease
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Agent-Based Modeling in Molecular Systems Biology.
Molecular systems orchestrating the biology of the cell typically involve a complex web of interactions among various components and span a vast range of spatial and temporal scales. Computational methods have advanced our understanding of the behavior of molecular systems by enabling us to test assumptions and hypotheses, explore the effect of different parameters on the outcome, and eventually guide experiments. While several different mathematical and computational methods are developed to study molecular systems at different spatiotemporal scales, there is still a need for methods that bridge the gap between spatially-detailed and computationally-efficient approaches. In this review, we summarize the capabilities of agent-based modeling (ABM) as an emerging molecular systems biology technique that provides researchers with a new tool in exploring the dynamics of molecular systems/pathways in health and disease
Quality control of mRNAs at the entry of the nuclear pore: Cooperation in a complex molecular system.
Despite extensive research on how mRNAs are quality controlled prior to export into the cytoplasm, the exact underlying mechanisms are still under debate. Specifically, it is unclear how quality control proteins at the entry of the nuclear pore complex (NPC) distinguish normal and aberrant mRNAs. While some of the involved components are suggested to act as switches and recruit different factors to normal versus aberrant mRNAs, some experimental and computational evidence suggests that the combined effect of the regulated stochastic interactions between the involved components could potentially achieve an efficient quality control of mRNAs. In this review, we present a state-of-the-art portrait of the mRNA quality control research and discuss the current hypotheses proposed for dynamics of the cooperation between the involved components and how it leads to their shared goal: mRNA quality control prior to export into the cytoplasm
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Torsional Behavior of Axonal Microtubule Bundles
Axonal microtubule (MT) bundles crosslinked by microtubule-associated protein (MAP) tau are responsible for vital biological functions such as maintaining mechanical integrity and shape of the axon as well as facilitating axonal transport. Breaking and twisting of MTs have been previously observed in damaged undulated axons. Such breaking and twisting of MTs is suggested to cause axonal swellings that lead to axonal degeneration, which is known as "diffuse axonal injury". In particular, overstretching and torsion of axons can potentially damage the axonal cytoskeleton. Following our previous studies on mechanical response of axonal MT bundles under uniaxial tension and compression, this work seeks to characterize the mechanical behavior of MT bundles under pure torsion as well as a combination of torsional and tensile loads using a coarse-grained computational model. In the case of pure torsion, a competition between MAP tau tensile and MT bending energies is observed. After three turns, a transition occurs in the mechanical behavior of the bundle that is characterized by its diameter shrinkage. Furthermore, crosslink spacing is shown to considerably influence the mechanical response, with larger MAP tau spacing resulting in a higher rate of turns. Therefore, MAP tau crosslinking of MT filaments protects the bundle from excessive deformation. Simultaneous application of torsion and tension on MT bundles is shown to accelerate bundle failure, compared to pure tension experiments. MAP tau proteins fail in clusters of 10-100 elements located at the discontinuities or the ends of MT filaments. This failure occurs in a stepwise fashion, implying gradual accumulation of elastic tensile energy in crosslinks followed by rupture. Failure of large groups of interconnecting MAP tau proteins leads to detachment of MT filaments from the bundle near discontinuities. This study highlights the importance of torsional loading in axonal damage after traumatic brain injury
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Nucleoporin's Like Charge Regions Are Major Regulators of FG Coverage and Dynamics Inside the Nuclear Pore Complex.
Nucleocytoplasmic transport has been the subject of a large body of research in the past few decades. Recently, the focus of investigations in this field has shifted from studies of the overall function of the nuclear pore complex (NPC) to the examination of the role of different domains of phenylalanine-glycine nucleoporin (FG Nup) sequences on the NPC function. In our recent bioinformatics study, we showed that FG Nups have some evolutionarily conserved sequence-based features that might govern their physical behavior inside the NPC. We proposed the 'like charge regions' (LCRs), sequences of charged residues with only one type of charge, as one of the features that play a significant role in the formation of FG network inside the central channel. In this study, we further explore the role of LCRs in the distribution of FG Nups, using a recently developed coarse-grained molecular dynamics model. Our results demonstrate how LCRs affect the formation of two transport pathways. While some FG Nups locate their FG network at the center of the NPC forming a homogeneous meshwork of FG repeats, other FG Nups cover the space adjacent to the NPC wall. LCRs in the former group, i.e. FG Nups that form an FG domain at the center, tend to regulate the size of the highly dense, doughnut-shaped FG meshwork and leave a small low FG density area at the center of the pore for passive diffusion. On the other hand, LCRs in the latter group of FG Nups enable them to maximize their interactions and cover a larger space inside the NPC to increase its capability to transport numerous cargos at the same time. Finally, a new viewpoint is proposed that reconciles different models for the nuclear pore selective barrier function