Thomas Cheatham

Thomas Cheatham
University of Utah | UOU · Department of Medicinal Chemistry

PhD

About

198
Publications
49,584
Reads
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39,968
Citations
Citations since 2016
46 Research Items
20855 Citations
201620172018201920202021202201,0002,0003,000
201620172018201920202021202201,0002,0003,000
201620172018201920202021202201,0002,0003,000
201620172018201920202021202201,0002,0003,000
Additional affiliations
January 2000 - present
University of Utah
Position
  • Professor (Associate)

Publications

Publications (198)
Article
Full-text available
Protein flexible loop regions were once thought to be simple linkers between other more functional secondary structural elements. However, as it becomes clearer that these loop domains are critical players in a plethora of biological processes, accurate conformational sampling of 3D loop structures is vital to the advancement of drug design techniq...
Article
Duplex DNA is modeled as canonical B-DNA displaying the characteristic Watson-Crick base pairs. A less common and short-lived pairing of the nucleobases is the Hoogsteen (HG) conformation. The low population of the HG base pairs (<1%) necessitates extended sampling times in order to analyze through unbiased molecular dynamics (MD) simulations. We h...
Article
Full-text available
The G-quadruplex is a noncanonical fold of DNA commonly found at telomeres and within gene promoter regions of the genome. These guanine-rich sequences are highly susceptible to damages such as base oxidation and depurination, leading to abasic sites. In the present work, we address whether a vacancy, such as an abasic site, in a G-quadruplex serve...
Article
Full-text available
Visualization of double stranded DNA in gels with the binding of the fluorescent dye ethidium bromide has been a basic experimental technique in any molecular biology laboratory for >40 years. The interaction between ethidium and double stranded DNA has been observed to be an intercalation between base pairs with strong experimental evidence. This...
Article
Full-text available
Copper-containing compounds known as Casiopeı́nas are biologically active molecules which show promising antineoplastic effects against several cancer types. Two possible hypotheses regarding the mode of action of the Casiopeı́nas have emerged from the experimental evidence: the generation of reactive oxygen species or the ability of the compounds...
Preprint
Full-text available
The SPIDAL (Scalable Parallel Interoperable Data Analytics Library) project was begun in Fall 2014 and has reached a technical completion in Fall 2020 with outreach activities continuing in 2021. The February Poster summarizes the 2020 status and activity very well with previous work through September 2018 summarized in a book chapter with extensiv...
Chapter
This paper reveals challenges in migrating C++ codes to GPUs using polyhedral compiler technology. We point to instances where reasoning about C++ constructs in a polyhedral model is feasible. We describe a case study using CPPTRAJ, an analysis code for molecular dynamics trajectory data. An initial experiment applied the CUDA-CHiLL compiler to key...
Chapter
Our project is at the interface of Big Data and HPC – High-Performance Big Data computing and this paper describes a collaboration between 7 collaborating Universities at Arizona State, Indiana (lead), Kansas, Rutgers, Stony Brook, Virginia Tech, and Utah. It addresses the intersection of High-performance and Big Data computing with several differe...
Article
Nucleic acids are highly charged macromolecules sensitive to their surroundings of water, salt, and other biomolecules. Molecular dynamics simulations with accurate biomolecular force fields provide a detailed atomistic view into DNA and RNA that has been useful to study the structure and dynamics of these molecules and their biological relevance....
Article
Advances in biomolecular simulation methods and access to large scale computer resources have led to a massive increase in the amount of data generated. The key enablers have been optimization and parallelization of the simulation codes. However, much of the software used to analyze trajectory data from these simulations is still run in serial, or...
Technical Report
Full-text available
Our project is at Interface Big Data and HPC -- High-Performance Big Data computing and this paper describes a collaboration between 7 collaborating Universities at Arizona State, Indiana (lead), Kansas, Rutgers, Stony Brook, Virginia Tech, and Utah. It addresses the intersection of High-performance and Big Data computing with several different app...
Conference Paper
Full-text available
Different parallel frameworks for implementing data analysis applications have been proposed by the HPC and Big Data communities. In this paper, we investigate three task-parallel frameworks: Spark, Dask and RADICAL-Pilot with respect to their ability to support data analytics on HPC resources and compare them to MPI. We investigate the data analys...
Article
Hopkins proposed an alternative and chirally distinct family of double-stranded DNA (dsDNA) models that have antiparallel chains with 5′→3′ senses opposite to those of the right-handed Watson–Crick (WC) family. Termed configuration II, this family of dsDNA models contains both right-handed (II-R) and left-handed (II-L) forms, with Z-DNA as an examp...
Data
Supplementary Information for "Defining a conformational ensemble that directs activation of PPAR gamma"
Article
Full-text available
The nuclear receptor ligand-binding domain (LBD) is a highly dynamic entity. Crystal structures have defined multiple low-energy LBD structural conformations of the activation function-2 (AF-2) co-regulator-binding surface, yet it remains unclear how ligand binding influences the number and population of conformations within the AF-2 structural ens...
Code
Amber is a suite of biomolecular simulation programs. It began in the late 1970's, and is maintained by an active develpment community. In particular, continuous constant pH MD (CpHMD) simulation is one of the major new features added in 2018. More information about CpHMD please refer to 2018 Amber reference manual for setting up the simulation an...
Article
Full-text available
The oncogenic gene product Bcr-Abl is the principal cause of chronic myeloid leukemia (CML) and though several therapies exist to curb the aberrant kinase activity of Bcr-Abl through targeting of the Abl kinase domain, these therapies are rendered ineffective by frequent mutations in the corresponding gene. It has been demonstrated that a designed...
Article
Dinucleotide monophosphates (DNMPs) have been described using various experimental approaches as flexible molecules which generate ensembles populating at least a small set of different conformations in solution. However, due to limitations of each approach in its ability to delineate the ensemble of conformations, an accurate and quantitative desc...
Article
Full-text available
Bioorthogonal dissociative reactions boast diverse potential applications in chemical biology and drug delivery. The reaction of benzonorbornadienes with tetrazines to release amines from carbamate leaving groups was recently introduced as a bioorthogonal bond-cleavage reaction. The present study aimed at investigating the scope of leaving groups t...
Article
Full-text available
The catechin family of molecules that are present in the leaves of green tea have been under investigation since the anti-oxidant and anti-inflammatory properties of tea were discovered. Among multiple proposed therapeutic targets of these molecules, the direct interaction with nucleic acids have been proposed and experimentally observedbut without...
Article
Full-text available
Though the structure of the substrate stem loop I (SLI)-stem loop V (SLV) kissing loop junction of the Varkud Satellite ribozyme has been experimentally characterized, the dynamics of this Mg²⁺-dependent loop-loop interaction have been elusive. Specifically, each hairpin loop contains a U-turn motif, but only SLV shows a conformational shift trigge...
Article
Full-text available
The interactions in the tertiary structure of a ribosomal RNA fragment in the GTPase Associating Center (GAC) have been experimentally studied, but the roles of the bound and diffuse cations in its folding pathway have not yet been fully elucidated. Melting experiments have shown that the temperature of the first of the two distinguishable transiti...
Article
We report the application of thiol-yne/thiol-ene reactions to synthesize mono- and bicyclic stapled peptides and proteins. We first developed a thiol-ene based peptide stapling method in aqueous conditions. This method enabled us to efficiently staple recombinantly expressed coil-coiled proteins. The resulting stapled protein demonstrates higher st...
Article
Reliable representation of the B-DNA base pair step twist is one of the crucial requirements for theoretical modeling of DNA supercoiling and other biologically relevant phenomena in B-DNA. It has long been suspected that the twist is inaccurately described by current empirical force fields. Unfortunately, comparison of simulation results with expe...
Article
An experimentally well-studied model of RNA tertiary structures is a 58mer rRNA fragment known as GTPase Associating Center (GAC) RNA, in which a highly negative pocket walled by phosphate oxygens is stabilized by a chelated cation. Although such deep pockets with more than one direct phosphate to ion chelation site are normally found to include ma...
Article
Full-text available
Significance The cyanobactin prenyltransferases serve as a tool kit for regioselective and chemoselective peptide and protein modifications, in which each enzyme can catalyze the same chemistry on an enormous number of different substrates. Installation of a minimal motif is sufficient to direct modifications on any peptide substrate, which can alt...
Article
The oncoprotein Bcr-Abl is the cause of chronic myeloid leukemia (CML). Current therapies target the tyrosine kinase domain of Bcr-Abl, but due to their non-curative nature, resistance to these drugs is common. Therefore, new treatments are needed for those patients refractive to available therapies. Bcr-Abl homo-oligomerization via its N-terminal...
Article
The utility of molecular dynamics (MD) simulations to model biomolecular structure, dynamics, and interactions, have witnessed enormous advance in recent years due to the availability of optimized MD software and access to significant computational power including GPU multicore computing engines and other specialized hardware. This has led research...
Article
We compare the performance of five magnesium (Mg(2+)) ion models in simulations of an RNA stem-loop which has an experimentally determined divalent ion dependent conformational shift. We show that despite their differences in parameterization and resulting van der Waals terms, including differences in the functional form of the nonbonded potential,...
Article
Long time scale molecular dynamics (MD) simulations of biological systems are becoming increasingly commonplace due to the availability of both large-scale computational resources and significant advances in the underlying simulation methodologies. Therefore, it is useful to investigate and develop data mining and analysis techniques to quickly and...
Article
Full-text available
The structure of double-stranded DNA (dsDNA) is sensitive to solvent conditions. In solution, B-DNA is the favored conformation under physiological conditions, while A-DNA is the form found under low water activity. The A-form is induced locally in some protein-DNA complexes, and repeated transitions between the B- and A-forms have been proposed to...
Article
s: AACR Special Conference: Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; November 9-12, 2015; Fort Lauderdale, Florida The purpose of this study is to investigate how EWS/FLI transcriptionally activates gene targets via polymorphic GGAA microsatellites. Ewing Sarcoma is a pediatric bone malignanc...
Chapter
A wide variety of experimental and simulation approaches have converged to provide an atomic level and a detailed view of DNA structure and dynamics and how these properties are altered as a function of sequence and environment. Here we present a series of DNA characteristics observed as a function of sequence. This information can be used to furth...
Article
Full-text available
Replication of the HIV-1 virus requires reverse transcription of the viral RNA genome, a process that is specifically initiated by human tRNA3Lys packaged within the infectious virion. The primary binding site for the tRNA involves the 3’ 18 nucleotides with an additional interaction between an adenine rich loop (A-loop) in the template and the ant...
Article
Z-DNA duplexes are a particularly complicated test case for current force fields. We performed a set of explicit solvent molecular dynamics (MD) simulations with various AMBER force field parametrizations including our recent refinements of the ε/ζ and glycosidic torsions. None of these force fields described the ZI/ZII and other backbone substates...
Article
BI and BII conformational sub states in the DNA backbone typify canonical B-form DNA. The BI and BII sub states are important for structural variation of DNA and have been implicated in protein-nucleic acid recognition mechanisms. Recent refinements have been made to nucleic acid force fields employed in molecular dynamics simulations that demonstr...
Article
Full-text available
Biomolecular simulations aim to simulate structure, dynamics, interactions, and energetics of complex biomolecular systems. With the recent advances in hardware, it is now possible to use more complex and accurate models, but also reach time scales that are biologically significant. Molecular simulations have become a standard tool for toxicology a...
Article
Full-text available
The Varkud Satellite RNA contains a self-cleaving ribozyme that has been shown to function independently of its surroundings. This 160 nucleotide ribozyme adopts a catalytically active tertiary structure that includes a kissing hairpin complex formed by Stem-loop I and Stem-loop V (SLV). The five-nucleotide 5'-rUGACU loop of the isolated SLV has be...
Article
Most existing treatments of induced dipoles in polarizable molecular mechanics force field calculations use either the self-consistent variational method, which is solved iteratively, or the "direct" approximation that is non-iterative as a result of neglecting coupling between induced dipoles. The variational method is usually implemented using as...
Article
We compare the performance of two different RNA force fields in four water models in simulating the conformational ensembles r(GACC) and r(CCCC). With the increased sampling facilitated by multidimensional replica exchange molecular dynamics (M-REMD), populations are compared to NMR data to evaluate force field reliability. The combination of AMBER...
Article
Full-text available
Recent modifications and improvements to standard nucleic acid force fields have attempted to fix problems and issues that have been observed as longer timescale simulations have become routine. Although previous work has shown the ability to fold the UUCG stem-loop structure, until now no group has attempted to quantify the performance of current...
Article
Full-text available
The family of anticancer complexes that include the transition metal copper known as Casiopeínas® shows promising results. Two of these complexes are currently in clinical trials. The interaction of these compounds with DNA has been observed experimentally and several hypotheses regarding the mechanism of action have been developed, and these inclu...
Article
The field of biomolecular simulation has matured to where detailed, accurate, and functionally relevant information that complements experimental data about the structure, dynamics, and interactions of biomolecules can now be routinely discovered. This has been enabled by access to large-scale and heterogeneous high-performance computing resources,...
Article
This unit presents an overview of computer simulation techniques as applied to nucleic acid systems, ranging from simple in vacuo molecular modeling techniques to more complete all-atom molecular dynamics treatments that include an explicit representation of the environment. The third in a series of four units, this unit focuses on critical issues...
Article
Full-text available
DNA helices display a rich tapestry of motion on both short (<100 ns) and long (>1 ms) timescales. However, with the exception of mismatched or damaged DNA, experimental measures indicate that motions in the 1 μs to 1 ms range are effectively absent, which is often attributed to difficulties in measuring motions in this time range. We hypothesized...
Article
Full-text available
We present the results of microsecond molecular dynamics simulations carried out by the ABC group of laboratories on a set of B-DNA oligomers containing the 136 distinct tetranucleotide base sequences. We demonstrate that the resulting trajectories have extensively sampled the conformational space accessible to B-DNA at room temperature. We confirm...
Article
Full-text available
Background: The structure and dynamics of DNA are critically related to its function. Molecular dynamics simulations augment experiment by providing detailed information about the atomic motions. However, to date the simulations have not been long enough for convergence of the dynamics and structural properties of DNA. Methods: Molecular dynamic...
Article
A racemic, prenylated polyketide dimer, oxazinin A (1), was isolated from a novel filamentous fungus in the class Eurotiomycetes, and its structure was elucidated spectroscopically. The pentacyclic structure of oxazinin A (1) is a unique combination of benzoxazine, isoquinoline, and a pyran ring. Oxazinin A (1) exhibited antimycobacterial activity...
Article
Full-text available
We have carried out extended set of μs-scale explicit solvent MD simulations of all possible G-triplexes which can participate in folding pathways of the human telomeric quadruplex. Our study accumulates almost 60 μs of simulation data, which is by about three orders of magnitude larger sampling compared to the earlier simulations of human telomeri...