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(1 - 9 of 9)
CHEMISTRY OF BUCKYBOWL FROM CLOSED-SHELL TO OPEN-SHELL
Title
CHEMISTRY OF BUCKYBOWL FROM CLOSED-SHELL TO OPEN-SHELL
Creator
Li, Jingbai
Date
2019
Description
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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Simple Entropy Terms for End-Point Binding Free Energy Calculations
Title
Simple Entropy Terms for End-Point Binding Free Energy Calculations
Creator
Menzer, William Michael
Date
2019
Description
We introduce a number of computationally inexpensive modifications to the MM/PBSA and MM/GBSA estimators for binding free energies, which are...
Show moreWe introduce a number of computationally inexpensive modifications to the MM/PBSA and MM/GBSA estimators for binding free energies, which are based on average receptor−ligand interaction energies in simulations of a noncovalent complex, to improve the treatment of entropy: second- and higher-order terms in a cumulant expansion and a confining potential on ligand external degrees of freedom. We also consider a filter for snapshots where ligands have drifted from the initial binding pose. The variations were tested on six sets of systems for which binding modes and free energies have previously been experimentally determined. For some data sets, none of the tested estimators led to results significantly correlated with measured free energies. In data sets with nontrivial correlation, a ligand RMSD cutoff of 3 Å and a second-order truncation of the cumulant expansion was found to be comparable or better than the average interaction energy by several statistical metrics.
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Efficiency of Stratification for Ensemble Reduction based on docking scores
Title
Efficiency of Stratification for Ensemble Reduction based on docking scores
Creator
Zhang, Hexi
Date
2018
Description
Molecular docking has been widely used in structure-based drug design to virtually screen large chemical libraries to predict the prefer...
Show moreMolecular docking has been widely used in structure-based drug design to virtually screen large chemical libraries to predict the prefer conformations ligands that could bind the target site. Protein flexibility is a major issue that could be solved by ensemble docking which is docking to ‘ensemble’ of protein rigid conformations, such as snapshots obtained by molecular dynamics simulations. Our group has developed a method called ‘Efficiency of Stratification’ to evaluate a number of common snapshot selection strategies using a quality metric from stratified sampling (Xie et al. [19]). Docking was performed to four proteins and with each ligand numbers sets of up to five hundred ligands. In this paper, we generated distance matrices based on docking score to analysis the performance of the efficiency of stratification method. We observed that most docking score based score-based distance matrices have had better performance than structure-based distance matrices and with including any structure-based component overwhelms the docking-score component. Only a few ligands are required to get a good distance matrix.
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Implicit ligand theory: binding free energy calculations based on multiple rigid receptor snapshots
Title
Implicit ligand theory: binding free energy calculations based on multiple rigid receptor snapshots
Creator
Xie, Bing
Date
2018
Description
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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Computational study on the heme scavenging ability of Staphylococcus aureus IsdH receptor: Utilizing molecular dynamics to understand an unknown mechanism
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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THE INTERACTION BETWEEN COINAGE OR ALKALI METALS AND POLYAROMATIC HYDROCARBONS
Title
THE INTERACTION BETWEEN COINAGE OR ALKALI METALS AND POLYAROMATIC HYDROCARBONS
Creator
Liu, Shuyang
Date
2020
Description
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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USING COMPUTATIONAL MOLECULAR MODELING TO STUDY TRANSPORT PROCESSES OF INTEREST IN SEPARATIONS
Title
USING COMPUTATIONAL MOLECULAR MODELING TO STUDY TRANSPORT PROCESSES OF INTEREST IN SEPARATIONS
Creator
Wang, Xiaoyu
Date
2020
Description
Separation processes are widely used in chemical productions. The further development of membrane-based separation processes, compared with...
Show moreSeparation processes are widely used in chemical productions. The further development of membrane-based separation processes, compared with thermal separations, can lead to significant energy savings in chemical process industries. However, the main obstacle of experiments is that many separation processes are not well understood at the fundamental molecular level. In this dissertation, we use computational molecular modeling tools, mainly classical molecular dynamics (MD), to clarify molecular forces and provide detail at a molecular level, which can aid in the understanding of transport process and designing materials for a proposed application.In the first study, we investigated separation of water/alcohol vapor using zeolite membranes. Experimentally, the separation of water/isopropanol (IPA) mixtures shows a dramatic decrease in selectivity due to increase of IPA flux as the feed water concentration decrease when using the sodium A zeolite membrane. We used molecular dynamics simulations to help our experimental collaborators understand these puzzling results. The MD results reveal that the water molecules gather around the defect pores on the zeolite membrane, which stops the IPA from going through the membrane and has a positive effect on separation.Then, we studied the HPLC used to separate chiral drug mixtures. One popular chiral stationary phase, amylose tris(3,5-dimethylphenyl carbamate) (ADMPC), has been investigated using both experimental and computational methods; however, the dynamic nature of the interaction between enantiomers and ADMPC, as well as the solvent effects on the ADMPC-enantiomer interaction, are currently absent from the chiral recognition mechanism. We used MD simulations to model the ADMPC in different solvents to elucidate the chiral recognition mechanism from a new dynamic perspective. The ADMPC is found to hold the left-handed helical structure in both methanol and heptane/IPA (90/10); however, the ADMPC has a more extended average structure in heptane/IPA. We developed a model where the ADMPC atoms were restricted in the MD simulation. To better understand the molecular dynamic chiral recognition that provides the retention factor and the elution order in HPLC, we examined hydrogen bonding lifetimes, and mapped out ring-ring interactions between the drugs and the ADMPC. We discover several MD metrics related to hydrogen-bonding lifetimes and correlate them with HPLC results. One metric provides a prediction of the correct elution order 90%, and the ratios of these quantities for the enantiomers provide linear correlation (0.85 coefficient) with experimental retention factors.In the following study, we presented an improved model wherein multiple ADMPC polymer strands are coated on an amorphous silica slab. Using various MD techniques, we successfully coated ADMPCs onto the surface without losing the structural character of the backbone in the solvent. This model provides more opportunities for chiral molecules interacting with ADMPC, resulting in a better agreement compared with experiment when using the overall average metric. The new model also provides the possibility for drug molecules to interact with two polymer strands simultaneously, which is not possible in the previous single-strand model. For a better understanding of why some metrics are better predictors than others, we used charts of the distribution of hydrogen bonding lifetimes to display the information for various donor-acceptor pairs. The results are more consistent than the previous models and resolves the problematic cases of thalidomide and valsartan.Besides the membrane-based separations, immiscible liquid-liquid equilibrium states were also studied. We successfully predicted results based on MD simulations and showed comparable accuracy with experimental data. This method has applications in liquid-liquid extraction which is widely used in industrial separation process.
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AN EXPLORATION INTO THE EFFECTS OF CHROMATIN STRUCTURAL PROTEINS ON THE DYNAMICS AND ENERGETIC LANDSCAPE OF NUCLEOSOME ARCHITECTURES
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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SEPARATING NOBLE GASES SUCH AS KRYPTON AND XENON FROM NUCLEAR POWER PLANTS OFF-GAS USING DD3R ZEOLITIC MEMBRANES: A COMPUTATIONAL MOLECULAR DYNAMICS STUDY
Title
SEPARATING NOBLE GASES SUCH AS KRYPTON AND XENON FROM NUCLEAR POWER PLANTS OFF-GAS USING DD3R ZEOLITIC MEMBRANES: A COMPUTATIONAL MOLECULAR DYNAMICS STUDY
Creator
BASHMMAKH, BANDAR JAMAL S.
Date
2021
Description
Noble gas fission products generated within nuclear power reactors, such as Kr and Xe, are currently discharged into the atmosphere. This...
Show moreNoble gas fission products generated within nuclear power reactors, such as Kr and Xe, are currently discharged into the atmosphere. This practice has a major economic drawback because of the high value associated with some of these gases. Zeolites, nanoporous materials suitable for gas separation processes, have become of major interest due to the potentially high selectivity for such separations. We have used nonequilibrium molecular dynamics to investigate the separation performance of DD3R framework zeolitic membranes (using LAMMPS software package) for such separations. Our studies have shown that the DD3R membrane shows promise for high selectivity ratios of Kr over Xe. The effects of pressure, temperature and pure vs. mixture gas feed conditions are studied in this work to understand at the molecular level the mechanisms of these (Kr/Xe) separations. MD runs show an agreement with most experimental trends in the permeation of Kr/Xe pure and mixed gases using DD3R zeolite with high separation factor, despite the absence of Xe complete permeation through the membrane because of MD timescale limitation, signaling much slower diffusion in comparison to Kr which is a desired trend in looking for high separation factors.
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