EXPLORING THE EFFECTS OF PHYSIOLOGICAL ENVIRONMENT ON AMYLOID AGGREGATION

dc.contributor.advisorMatysiak, Silvinaen_US
dc.contributor.authorSahoo, Abhilashen_US
dc.contributor.departmentBiophysics (BIPH)en_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2022-09-27T05:31:14Z
dc.date.available2022-09-27T05:31:14Z
dc.date.issued2022en_US
dc.description.abstractMolecular level self-assembly/aggregation processes are common in biomolecular systems. Specifically, aggregation of protein molecules results in formation of amyloid deposits, that has been associated with neuronal dysfunction leading up to neurodegeneration. The protein aggregation is often influenced by several external physiological features, which can modulate this pathological process in a specific or non-specific manner. This thesis aims to elucidate the role of such factors in amyloid aggregation in the context of neurodegeneration. As test cases, we have focused on different fragments of Amyloid-beta peptide and Huntingtin protein and explored common interaction schemes in the presence of phospholipid membranes, solvated glucose molecules and added trailing sequences. Phospholipid membranes, composed of a heterogeneous distribution of lipid molecules, serve as packaging envelopes in cellular systems. But several studies have suggested a role of cellular membranes in abetting protein aggregation in neurodegenerative diseases. The first section of this thesis explores Amyloid-beta 16-22 aggregation in the presence of membranes. Lipid membranes have been shown to modulate peptide aggregation in a charge dependent manner with anionic membranes promoting faster peptide aggregation into ordered fibrillar structures compared to zwitterionic membranes. In this work, we evaluate the role of this electrostatic membrane headgroup charge on Amyloid-beta 16-22 peptide aggregation with model lipid membranes composed of POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) and POPS (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine) lipids. Beyond, membrane charge, membrane's physical organization can also affect peptide-peptide and peptide-membrane interactions. Here, we have curated the effects of applied surface-tension, as a proxy for membrane curvature, on peptide fibrillation propensities. Apart from ordered structures such as membranes, solvated small molecules are a large class of molecules that can affect aggregation patterning by affecting peptides through both specific and non-specific interactions. The second section of this thesis explores Amyloid-beta 16-22 aggregation in varying hyperglycemic conditions, to draw correlations between Alzheimer's disease and type 2 diabetes. Here, we discovered that the glucose prefers partitioning onto the aggregate-water interface in a specific manner, leading to a loss in rotational entropy that propels peptide aggregation. In the final section, we discuss the case of pathological peptide aggregation in the case of Huntington's disease. Broadly, Huntinting protein's N-terminal region which consists of 17-residue N-terminal domain (N17) and the following Glutamine repeat tract (Poly-Q) are our objects of interest and associated with pathological aggregation. The aggregation landscape of N17 is analyzed in presence of added different lengths of trailing Poly-Q tract and the presence of curved membranes. We have approached our research through a computational lens using molecular dynamics simulations. To address the relevant concerns of large spatio-temporal scales necessary to study peptide aggregation systems with molecular simulations, we have developed a coarse-grained forcefield (ProMPT: Protein Model with Polarizability and Transferability) that uses reduced spatial resolution to accelerate phase-space exploration. The forcefield can capture secondary and tertiary folding of protein structures with minimal constraints, and is transferable across biomolecular systems without a need for re-parametrization. My dissertation presents a holistic picture of peptide aggregation and various physiological factors that affect it, with biomolecular simulation across multiple scales.en_US
dc.identifierhttps://doi.org/10.13016/rkkp-liio
dc.identifier.urihttp://hdl.handle.net/1903/29286
dc.language.isoenen_US
dc.subject.pqcontrolledBiophysicsen_US
dc.subject.pqcontrolledComputational chemistryen_US
dc.subject.pquncontrolledAggregationen_US
dc.subject.pquncontrolledAmyloid-betaen_US
dc.subject.pquncontrolledCoarse-graineden_US
dc.subject.pquncontrolledMolecular Dynamicsen_US
dc.titleEXPLORING THE EFFECTS OF PHYSIOLOGICAL ENVIRONMENT ON AMYLOID AGGREGATIONen_US
dc.typeDissertationen_US

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