Access Type

Open Access Dissertation

Date of Award

January 2025

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Physics and Astronomy

First Advisor

Yu-ming Mindy Huang

Abstract

Understanding the dynamics of protein–protein and protein–ligand interactions is critical for elucidating biological function and guiding drug discovery. However, many such processes involve rare events and high energy barriers that are difficult to capture with conventional molecular dynamics (MD). Enhanced sampling techniques extend the reach of MD, enabling access to biologically relevant transitions and thermodynamic properties. In the first project, Gaussian accelerated MD (GaMD) was used to study the MEIG1–PACRG complex, a key regulator of sperm flagellar assembly. Simulations of wildtype and mutant MEIG1 (W50A, Y68A) revealed mutation-specific disruptions to the binding interface and identified druggable pockets, particularly on PACRG. Virtual screening and MD simulations were then applied to identify small-molecule inhibitors targeting this complex, yielding promising candidates stabilized by hydrogen bonding and π-π stacking interactions. The second project used ligand GaMD (LiGaMD) to investigate the unbinding of linoleic acid from the SARS-CoV-2 spike protein. Simulations captured eight dissociation events and revealed two dominant pathways influenced by RBD gating and glycan dynamics, offering insights into ligand regulation of spike–ACE2 binding. In the third project, a new method called Multiple Parameter Replica Exchange GaMD (MP-Rex-GaMD) was developed to improve sampling efficiency and energetic reweighting. Benchmarking on dialanine, chignolin, and HIV protease demonstrated enhanced conformational exploration and accurate free energy recovery. Together, these projects highlight the power of enhanced sampling MD to uncover molecular mechanisms, inform inhibitor design, and advance methodological innovation in biomolecular simulation.

Download

Included in

Biophysics Commons

Share

COinS