ORCID

https://orcid.org/0009-0000-1838-9411

Date of Award

2025

Document Type

Thesis

Degree Name

MS in Chemistry

Department

Chemistry

First Advisor

Frank X Vázquez

Second Advisor

Joseph M Serafin

Third Advisor

Erica Jacobs

Abstract

This thesis aims to elucidate the molecular mechanisms by which nucleotide binding dictates the intrinsic dynamics and to understand the functional conformational changes of Human Dynamin-1 during the GTP hydrolysis cycle through the use of Elastic Network Models (ENM). A comprehensive understanding of this process is crucial given dynamin's role in clathrin-mediated endocytosis (CME). The research utilized both experimentally derived crystal structures and AlphaFold-predicted structures of dynamin, specifically examining the GTPase and Bundle Signaling Element (BSE) domains across nucleotide-free, GTP-bound, GDP-bound, and transition states. The essential features of the research methodology involved a multi-scale computational approach. Qualitative analyses were performed using ENM, including the Gaussian Network Model (GNM) to identify isotropic flexibility, and the Anisotropic Network Model (ANM) to characterize directional, large-scale conformational movements. These network models were complemented by Molecular Dynamics (MD) simulations, providing atomic-level, time-resolved insights into dynamic pathways. Principal Component Analysis (PCA) was then applied to MD trajectories to extract dominant collective motions and quantitatively validate the intrinsic dynamics predicted by ANM. The findings advance our understanding of how ligands and dimerization affect intrinsic motions, as well as what large-scale movements occur during hydrolysis. This research offers critical insight into molecular movements and can enhance the current understanding of vesicle dynamics and membrane fission.

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