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(1 - 5 of 5)
- Title
- CHEMISTRY OF BUCKYBOWL FROM CLOSED-SHELL TO OPEN-SHELL
- Creator
- Li, Jingbai
- Date
- 2019
- Description
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Buckybowl is an open geodesic polyaromatic molecule with unevenly distributed π-electron on its convex and concave surface, which leads to a...
Show moreBuckybowl is an open geodesic polyaromatic molecule with unevenly distributed π-electron on its convex and concave surface, which leads to a readily accessible π-surface for substitution reactions and complexation with various metals. Despite the diverse structures of buckybowl complexes observed in the previous experimental study, our computational work has shown that the π-surface of buckybowl always plays the most important role in the bonding. Modification of the π-surface by changing the size of conjugation and the curvature enable us to tune the bonding preference of the buckybowl surface and the stability of the complex. Our continued study has shown similar importance of the π-surface in functionalization of buckybowl with different electrophilic groups. Surprisingly, our investigation on buckybowl cations intrigued an original perspective of aromatic behavior of the π-surface. Our results have revealed an intrinsic nature of aromatic stabilization in polyaromatic cations, which is mainly attributed to the depletion of anti-aromaticity at the center ring. Further study showed an explicit correlation between the curvature of π-surface and the stability of adducts, aromatic behavior at center ring, as well as the spin distribution over polyaromatic moiety. By curving the π-surface, we have proposed several buckybowl radical adducts and confirmed their stability. These models provide an alternative strategy of developing polyaromatic spin carriers, which have a great potential in the manufacture of quantum bits. We believe our comprehensive theoretical study on versatile chemistry of buckybowl and related polyaromatic hydrocarbons can offer fundamental understanding and essential guidance for developing buckybowl-based electrode materials in the lithium-ion battery, organometallic building block, and spin electronic devices.
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- Title
- Implicit ligand theory: binding free energy calculations based on multiple rigid receptor snapshots
- Creator
- Xie, Bing
- Date
- 2018
- Description
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Binding affinity plays an important role in drug design. Accurate and fast prediction of binding free energies remains a major challenge for...
Show moreBinding affinity plays an important role in drug design. Accurate and fast prediction of binding free energies remains a major challenge for structure-based calculation. We have developed a fast free energy calculation program AlGDock and applied it to different systems. In this thesis, I will first demonstrate the feasibility of estimating protein-ligand binding free energies using multiple rigid receptor configurations on T4 lysozyme. Based on 576 snapshots extracted from six alchemical binding free energy calculations with a flexible receptor, binding free energies were estimated for a total of 141 ligands. For 24 ligands, the calculations reproduced flexible-receptor estimates with a correlation coefficient of 0.90 and a root mean square error of 1.59 kcal/mol. The accuracy of calculations based on Poisson-Boltzmann/Surface Area implicit solvent was comparable to previously reported free energy calculations. Then we evaluate a number of common snapshot selection strategies using a quality metric from stratified sampling, the efficiency of stratification, which compares the variance of a selection strategy to simple random sampling. For docking sets of over five hundred ligands to four different proteins of varying flexibility, we observe that for estimating ensemble averages and exponential averages, many clustering algorithms have similar performance trends: for few snapshots (less than 25), medoids are the most efficient while for a larger number, optimal (the allocation that minimizes the variance) and proportional(to the size of each cluster) allocation become more efficient. Proportional allocation appears to be the most consistently efficient for estimating minima. Finally, we attempted a blinded prediction challenge D3R and applied AlGDock on several systems. I will describe the performance of our calculation. Overall, the study shows that AlGDock can work well for predicting the binding affinities and it demonstrates a strategy for developing an understanding of protein-ligand interactions.
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- Title
- Computational study on the heme scavenging ability of Staphylococcus aureus IsdH receptor: Utilizing molecular dynamics to understand an unknown mechanism
- Creator
- Clayton, Joseph Alan
- Date
- 2021
- Description
-
Methicillin-resistant Staphylococcus aureus (MRSA) has become an infamous pathogen with infection rates that have declined slowly in recent...
Show moreMethicillin-resistant Staphylococcus aureus (MRSA) has become an infamous pathogen with infection rates that have declined slowly in recent years. S. aureus requires iron as a metabolic nutrient during infection and obtains this nutrient through an iron-regulated surface-determinant (Isd) system that extracts iron from the host’s heme stored in hemoglobin (Hb) through near iron transporter (NEAT) domains. This work concentrates on studying the second and third NEAT domains of IsdH by utilizing atomistic molecular dynamics to probe the heme scavenging process; in collaboration with the Clubb Group at UCLA, we discover key functional regions of IsdH and describe fundamental interdomain dynamics. In addition, I investigate a conventional computational method to describe protein dynamics and propose an alternative that aims to alleviate computational effort by incorporating experimental data.
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- Title
- THE INTERACTION BETWEEN COINAGE OR ALKALI METALS AND POLYAROMATIC HYDROCARBONS
- Creator
- Liu, Shuyang
- Date
- 2020
- Description
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Theoretical study on versatile chemistry of buckybowls and related polyaromatic hydrocarbons has been comprehensively accomplished and...
Show moreTheoretical study on versatile chemistry of buckybowls and related polyaromatic hydrocarbons has been comprehensively accomplished and documented. Polyaromatic hydrocarbons from simple double bond to fullerene C60, as one of major family in buckybowls has shown a wide potential in development of various specifically purposed materials. Complexes with coinage metals evidenced tunable donor ability of related polyaromatic systems’ π-surface. Moreover, functionalization with small ligands cations interact with these π-surface also show some patterns which have certain enlightenment to the experiment. By adding the methyl group on corannulene, to pursue the relationship between geometry and stabilization which provide an alternative strategy of developing. Further study of alkali metals interacts with annulene, continuously adding with crown ether to mimic experiment environment display an interesting pattern. In the end, extended topics of some applications with computational chemistry, such as the help of Raman spectrum of L-focus.
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- Title
- AN EXPLORATION INTO THE EFFECTS OF CHROMATIN STRUCTURAL PROTEINS ON THE DYNAMICS AND ENERGETIC LANDSCAPE OF NUCLEOSOME ARCHITECTURES
- Creator
- Woods, Dustin C
- Date
- 2022
- Description
-
Comprised of eight core histones wrapped around at least 147 base pairs of DNA, nucleosomes are the fundamental unit the chromatin fiber from...
Show moreComprised of eight core histones wrapped around at least 147 base pairs of DNA, nucleosomes are the fundamental unit the chromatin fiber from which long arrays are built to compact genetic information into the cell nucleus. Structural proteins, such as linker histones (LH) and centromere proteins (CENP), interact with the DNA to dictate the exact architecture of the fiber which can directly influence the regulation of epigentic processes. However, the mechanisms by which structural proteins affect these processes are poorly understood. In this thesis, I will explore the various way in which LHs and CENP-N affect nucleosome and, by extension, chromatin fiber dynamics. First, I present a series of simulations of nucleosomes bound to LHs, otherwise known as chromatosomes, with the globular domain of two LH variants, generic H1 (genGH1) and H1.0 (GH1.0), to determine how their differences influence chromatosome structures, energetics and dynamics. These simulations highlight the thermodynamic basis for different LH binding motifs, and details their physical and chemical effects on chromatosomes. Second, I examine how well the findings above translate from mono-nucleosomes to poly-nucleosome arrays. I present a series of molecular dynamics simulations of octa-nucleosome arrays, based on a cryo-EMstructure of the 30-nm chromatin fiber, with and without the globular domains of the H1 LH to determine how they influence fiber structures and dynamics. These simulations highlight the effects of LH binding on the internal dynamics and global structure of poly- nucleosome arrays, while providing physical insight into a mechanism of chromatin compaction. Third, I took a brief departure from LHs to study the effects that the centromere protein N (CENP-N) has on the poly-nucleosome systems. I present a series of molecular dynamics simulations of CENP-N and di-nucleosome complexes based on cryo- EM and crystal structures provided by Keda Zhou and Karolin Luger. Simulations were conducted with nucleosomes in complex with one, two, and no CENP-Ns. This work, in collaboration with the Karolin Luger Group (University of Colorado – Boulder) and the Aaron Straight Group (Stanford University), represents the first atomistic simulations of this novel complex, providing the foundation for a plethora of future research opportunities exploring centromeric chromatin the effect that its structure and dynamics have on epigenetics. Lastly, I return to the chromatosome to study how DNA sequence affects the free energy surface and detailed mechanism of LH transitions between binding modes. I used umbrella sampling simulations to produce PMFs of chromatosomes wrapped in three different DNA sequences: Widom 601, poly-AT, and poly-CG. This work, my final in the series, represents a culmination of my studies furthering the understanding of biophysical phenomena surrounding LHs and how they can be extrapolated towards epigentic mechanisms. I was able to report on the first PMFs illustrating a previously unknown transition and describe the transition mechanism as it depends on DNA sequence.
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