Dynamics of biomolecules: Dielectric spectrum of DNA and assembly of peptide fibrils
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The Ohio State University / OhioLINK
2018
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu15148316766429942021-08-03T07:05:08Z Dynamics of biomolecules: Dielectric spectrum of DNA and assembly of peptide fibrils Agnihotri, Mithila V., agnihotri Biophysics DNA dielectric molecular dynamics tau PHF6 Biomolecule dynamics underlie important biological processes. These are dicult to probe experimentally and molecular dynamics (MD) simulations can be used to study these processes at atomic resolution. In this work, we use MD to study two dierent processes - DNA dielectric response and polymorphic configurations of peptide fibrils implicated in neurodegenrative diseases.The frequency-dependent dielectric response of DNA has biomedical and biotechnological applications besides being an important determinant of its biological function. Hence the dielectric response of DNA has been studied since the 1940’s, from even before its atomic resolution structure was determined. The link between DNA dynamics on a molecular level and dielectric response still eludes scientists. These properties are not revealed by experimental data alone. Probing these properties using simulations has proved dicult as well due to large system size and long time-scales associated with their motions. Hence, one needs to accumulate very long trajectories, for which the storage requirements are actually more severe than the computational requirements needed to generate the trajectory.Recently, the dielectric spectra of short-chain DNA oligomers were measured, exhibiting an absorption peak corresponding to a 10ns timescale. This is the first time such data is available for oligomers small enough to be accessible to detailed molecular dynamics simulations. Recent attempts by other groups to extract the dielectric spectrum from simulation have proved inconclusive. To tackle these problems, we have re-formulated the theory of electrokinetic and dielectric processes in a way that enables calculation of dielectric properties from both equilibrium and non-equilibrium simulations using sparse sampling of data without compromising accuracy. We have validated our methods in model systems, and by demonstrating the convergence of the dielectric spectrum from an exceptionally long 5 microsecond trajectory for a DNA dodecamer solvated with 11257 water molecules.We also studied the structural characteristics of short peptide fibrils which provide insight about a class of neurodegenerative diseases called tauopathies. This set of clinically heterogenous diseases are all characterised by the presence of insoluble Tau aggregates which under under normal physiological conditions, is a soluble protein that stabilises neuronal microtubules. Tau aggregates in the dierent tauopathies have morphologically dierent characteristics. For example, Tau forms long fibrillar aggregates that appear as twisted ribbons in Alzheimer’s disease while it forms long tubules in Pick’s disease. It is useful to study the polymorphic fibril structures in order to design small molecules for differential disease diagnosis and treatment. We used MD to probe the structural basis for Tau polymorphic fibrils using a small hexapeptide segment from Tau shown to be important in fibril formation. We also provide insight into Tau aggregation mechanism by demonstrating in-silico spontaneous end-to-end annealing of small Tau peptide oligomers. 2018-06-14 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1514831676642994 http://rave.ohiolink.edu/etdc/view?acc_num=osu1514831676642994 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Biophysics DNA dielectric molecular dynamics tau PHF6 |
| spellingShingle |
Biophysics DNA dielectric molecular dynamics tau PHF6 Agnihotri, Mithila V., agnihotri Dynamics of biomolecules: Dielectric spectrum of DNA and assembly of peptide fibrils |
| author |
Agnihotri, Mithila V., agnihotri |
| author_facet |
Agnihotri, Mithila V., agnihotri |
| author_sort |
Agnihotri, Mithila V., agnihotri |
| title |
Dynamics of biomolecules: Dielectric spectrum of DNA and assembly of peptide fibrils |
| title_short |
Dynamics of biomolecules: Dielectric spectrum of DNA and assembly of peptide fibrils |
| title_full |
Dynamics of biomolecules: Dielectric spectrum of DNA and assembly of peptide fibrils |
| title_fullStr |
Dynamics of biomolecules: Dielectric spectrum of DNA and assembly of peptide fibrils |
| title_full_unstemmed |
Dynamics of biomolecules: Dielectric spectrum of DNA and assembly of peptide fibrils |
| title_sort |
dynamics of biomolecules: dielectric spectrum of dna and assembly of peptide fibrils |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2018 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1514831676642994 |
| work_keys_str_mv |
AT agnihotrimithilavagnihotri dynamicsofbiomoleculesdielectricspectrumofdnaandassemblyofpeptidefibrils |
| _version_ |
1719453317172559872 |