Date of Award
Doctor of Philosophy (PhD)
Although the amount of experimental and theoretical protein studies have grown exponentially in recent years, we still do not have enough knowledge about the folding dynamics and structural properties of proteins to fold a protein from its primary sequence. The hydrophobic effect of protein cores is a dominant driving force of the protein folding process. In my work, I utilize high-quality X-ray crystallography and solution NMR structures, along with an atomistic model of proteins, to study the structural properties and fluctuations of protein cores. This thesis presents three computational and theoretical studies of proteins and their core regions. In the first study, I propose a new metric to quantify the packing properties of protein core based on the void structure of the core. I compare the void analysis between multiple systems, including experimentally obtained X-ray crystal structures, randomly packed amino acids, and mono-disperse sphere packing systems. I find that the amino acid packing systems are similar to X-ray crystal structures not only in their packing fractions but also in their void structures. In the meantime, they are different from all other packing systems. For the second project, I study the fundamental differences between solution NMR structures and X-ray crystallography structures. I show that the fluctuation observed in NMR bundle is greater than that in X-ray crystallography structures, and the difference between NMR bundle and X-ray structure are small but significant. I demonstrate that NMR structures are packed more densely in the core region than X-ray structures. Along with the thermalized amino acid packing model, I propose that the difference between NMR and X-ray structures comes from the different temperatures that the two experiments are performed at. In the last project, I study three commonly used molecular dynamics force fields and their capability of recapitulating experimental fluctuations. Although all three force fields are parametrized using NMR experimental structures, they appear to have much larger fluctuation both globally and in the core when comparing to X-ray duplicates and NMR bundles. The replica exchange molecular dynamics simulation reveals that although the experimental structure is one of the energy minima of the force field, there exist other energy minima that are more favorable.
Mei, Zhe, "Computational Studies of Proteins:\\ Void analyses, NMR and X-ray structures, Fluctuations in protein structure measured using molecular dynamics simulations" (2021). Yale Graduate School of Arts and Sciences Dissertations. 90.