자료유형  

 학위논문

Control Number  

0017164238

International Standard Book Number  

9798346858430

Dewey Decimal Classification Number  

541

Main Entry-Personal Name  

Chan, Arnold M.

Publication, Distribution, etc. (Imprint  

[S.l.] : Northwestern University., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

216 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-06, Section: B.

General Note  

Advisor: Chen, Lin X.

Dissertation Note  

Thesis (Ph.D.)--Northwestern University, 2024.

Summary, Etc.  

요약The three-dimensional structure of a biological macromolecule (BMM) determines its biological function. Protein folding has been at the forefront of biophysical research for decades and led to the development of numerous experimental and computational methods to characterize not only structure but also mechanisms. The folding pathways and structural dynamics of BMMs still possess many unmapped and unknown transient conformations, which are relevant to understanding how critical functional structures are formed or lost. Studying transient conformational intermediates and mechanisms is important for advancing our knowledge of diseases and developing new biotechnology.Time-Resolved X-ray solution scattering (TRXSS) is an emerging technique that captures the structural dynamics of BMMs after an environmental perturbation. Structural dynamics in biological systems (proteins, nucleic acids, lipid membranes) are triggered by environmental conditions, such as temperature or pH. TRXSS can capture global structural information with microseconds and milliseconds resolution, so it offers an advantage over conventional spectroscopy, reliant on local structural probes. Laser-triggered pump-probe TRXSS has been utilized for characterizing model protein systems and has not yet been applied to intrinsically disordered proteins nor other classes of BMMs.This work applies laser-triggered TRXSS to study the fast structural dynamics of BMMs not yet explored by this method of biophysical characterization. The Trp-cage miniprotein was studied with temperature-jump (T-jump) TRXSS. Trp-cage is a fast-folding miniprotein that has long been simulated with molecular dynamics (MD); however, the experimental benchmarks for its microsecond-timescale structural dynamics are lacking. To expand the application of TRXSS beyond protein systems, this work reports the first pump-probe pH-jump TRXSS experiment to directly observe the pH-induced folding dynamics of i-motif DNA, which is a common nucleic acid motif in programmable nanotechnology. Beyond unimolecular BMM systems, this work also applied T-jump TRXSS to understanding drug delivery mechanisms, directly observing the phase transition dynamics in liquid crystalline lipid nanoparticles. Along with determining new transient intermediates for these BMMs, novel data analysis and modeling pipelines were developed to address challenges that arose from these new experiments. A noise-weighted global analysis method was developed to allow for the simultaneous modeling of BMM TRXSS results with variable temporal and spatial uncertainty. Additionally, an ensemble structural fitting routine with a genetic algorithm architecture was developed to accurately model the kinetic ensemble signatures, ultimately providing a systematic solution to bridging MD simulations with experimental results. The work described in this dissertation (1) extends the feasibility of pump-probe TRXSS to broader biological contexts (intrinsically disordered proteins, nucleic acids, and lipid nanoparticles) and (2) expands the structural analysis pipeline to model heterogenous structural ensembles from TRXSS.

Subject Added Entry-Topical Term  

Physical chemistry.

Subject Added Entry-Topical Term  

Chemistry.

Subject Added Entry-Topical Term  

Computational chemistry.

Subject Added Entry-Topical Term  

Biophysics.

Index Term-Uncontrolled  

Biological macromolecule

Index Term-Uncontrolled  

Computational biology

Index Term-Uncontrolled  

Structural dynamics

Index Term-Uncontrolled  

X-ray scattering

Index Term-Uncontrolled  

Lipid membranes

Added Entry-Corporate Name  

Northwestern University Chemistry

Host Item Entry  

Dissertations Abstracts International. 86-06B.

Electronic Location and Access  

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Control Number  

joongbu:658009