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Search Results: 1 - 10 of 412169 matches for " William M. Southerland "
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Investigation of Chiral Molecular Micelles by NMR Spectroscopy and Molecular Dynamics Simulation  [PDF]
Kevin F. Morris, Eugene J. Billiot, Fereshteh H. Billiot, Kenny B. Lipkowitz, William M. Southerland, Yayin Fang
Open Journal of Physical Chemistry (OJPC) , 2012, DOI: 10.4236/ojpc.2012.24032
Abstract: NMR spectroscopy and Molecular Dynamics (MD) simulation analyses of the chiral molecular micelles poly-(Sodium Undecyl-(L,L)-Leucine-Valine) (poly-SULV) and poly-(Sodium Undecyl-(L,L)-Valine-Leucine) (poly-(SUVL)) are reported. Both molecular micelles are used as chiral selectors in electrokinetic chromatography and each consists of covalently linked surfactant chains with chiral dipeptide headgroups. To provide experimental support for the structures from MD simulations, NOESY spectra were used to identify protons in close spatial proximity. Results from the NOESY analyses were then compared to radial distribution functions from MD simulations. In addition, the hydrodynamic radii of both molecular micelles were calculated from NMR-derived diffusion coefficients. Corresponding radii from the MD simulations were found to be in agreement with these experimental results. NMR diffusion experiments were also used to measure association constants for polar and non-polar binaphthyl analytes binding to both molecular micelles. Poly (SUVL) was found to bind the non-polar analyte enantiomers more strongly, while the more polar analyte enantiomers interacted more strongly with poly(SULV). MD simulations in turn showed that poly(SULV) had a more open structure that gave greater access for water molecules to the dipeptide headgroup region.
A Molecular Dynamics Simulation Study of Two Dipeptide Based Molecular Micelles: Effect of Amino Acid Order  [PDF]
Kevin F. Morris, Eugene J. Billiot, Fereshteh H. Billiot, Kenny B. Lipkowitz, William M. Southerland, Yayin Fang
Open Journal of Physical Chemistry (OJPC) , 2013, DOI: 10.4236/ojpc.2013.31004

Molecular dynamics (MD) simulations were used to compare the structures of the chiral molecular micelles (MM) poly-(sodium undecyl-(L,L)-leucine-valine) (poly(SULV)) and poly-(sodium undecyl-(L,L)-valine-leucine) (poly (SUVL)). Both MM contained polymerized surfactant monomers terminated by chiral dipeptide headgroups. The study was undertaken to investigate why poly(SULV) is generally a better chiral selector compared to poly(SUVL) in electrokinetic chromatography separations. When comparing poly(SULV) to poly(SUVL), poly(SULV) had the more conformational flexible dipeptide headgroup and hydrogen bond analyses revealed that the poly(SULV) headgroup conformation allowed a larger number of intramolecular hydrogen bonds to form between monomer chains. In addition, a larger number of water molecules surrounded the chiral centers of the poly(SULV) molecular micelle. Poly(SULV) was also found to have a larger solvent accessible surface area (SASA) than poly(SUVL) and fluctuations in the poly(SULV) SASA during the MD simulation allowed dynamic monomer chain motions expected to be important in chiral recognition to be identified. Finally, approximately 50% of the Na+ counterions were found in the first three solvation shells surrounding both MM, with the remainder located in the bulk. Overall the MD simulations point to both greater headgroup flexibility and solvent and analyte access to the chiral centers of the dipeptide headgroup as factors contributing to the enhanced chiral selectivity observed with poly(SULV).

Ligand Binding and Circular Permutation Modify Residue Interaction Network in DHFR
Zengjian Hu,Donnell Bowen,William M Southerland ,Antonio del Sol,Yongping Pan,Ruth Nussinov,Buyong Ma
PLOS Computational Biology , 2007, DOI: 10.1371/journal.pcbi.0030117
Abstract: Residue interaction networks and loop motions are important for catalysis in dihydrofolate reductase (DHFR). Here, we investigate the effects of ligand binding and chain connectivity on network communication in DHFR. We carry out systematic network analysis and molecular dynamics simulations of the native DHFR and 19 of its circularly permuted variants by breaking the chain connections in ten folding element regions and in nine nonfolding element regions as observed by experiment. Our studies suggest that chain cleavage in folding element areas may deactivate DHFR due to large perturbations in the network properties near the active site. The protein active site is near or coincides with residues through which the shortest paths in the residue interaction network tend to go. Further, our network analysis reveals that ligand binding has “network-bridging effects” on the DHFR structure. Our results suggest that ligand binding leads to a modification, with most of the interaction networks now passing through the cofactor, shortening the average shortest path. Ligand binding at the active site has profound effects on the network centrality, especially the closeness.
Interaction Energy Analysis of Nonclassical Antifolates with Pneumocystis carinii Dihydrofolate Reductase
Conrad Pitts,Jian Yin,Donnell Bowen,Celia J. Maxwell,William M. Southerland
International Journal of Molecular Sciences , 2002, DOI: 10.3390/i3111188
Abstract: The x-ray structure of the Pneumocystis carinii dihydrofolate reductase (DHFR):trimethoprim:NADPH ternary complex obtained from the Protein Databank was used as a structural template to generate models for the following complexes: P. carinii DHFR:piritrexim:NADPH, P. carinii DHFR:epiroprim:NADPH, and P. carinii DHFR:trimetrexate:NADPH. Each of these complexes, including the original trimethoprim complex was then modeled in 60 angstrom cubes of explicit water and minimized to a rms gradient between 1.0 to 3.0 x 10-5 kcal/angstrom. Subsequently, each antifolate structure was subdivided into distinct substructural regions. The minimized complexes were used to calculate interaction energies for each intact antifolate and its corresponding substructural regions with the P. carinii DHFR binding site residues, the DHFR protein, the solvated complex ( which consists of P. carinii DHFR, NADPH, and solvent water), solvent water alone, and NADPH. Antifolate substructural regions which contained nitrogen and carbon atoms in an aromatic environment (i. e. the pteridyl, pyridopyrimidinyl, and diaminopyrimidinyl subregions) contributed most to the stability of antifolate interactions, while interaction energies for the hydrocarbon aromatic rings, methoxy, and ethoxy groups were much less stable. Additionally, interaction energy analyses were calculated for carbon and nitrogen atoms of the pteridyl, pyridopyrimidinyl, and diaminopyrimidinyl subregions and for the carbon and oxygen atoms of methoxy and ethoxy subregions. The contributions of hydrogen atoms were included with those of the carbon, nitrogen and oxygen atoms to which they are attached. These analyses revealed that the carbon atoms of the pteridyl, pyridopyrimidinyl, and diaminopyrimidinyl subregions generally contributed most to the stability of those regions. Carbon atoms also contributed favorably to the stability of the methoxy group interactions. Those substructural regions which exhibit relatively unfavorable interaction energies may constitute important modification targets in the design of improved P. carinii DHFR inhibitors. Interaction energies for different groups of atoms within the substructural regions suggest strategies for modification of the substructural regions.
Q-VE-OPh, a Negative Control for O-Phenoxy-Conjugated Caspase Inhibitors
Benjamin Southerland, Kashmira Kulkarni-Datar, Chanel Keoni, Rebecca Bricker, William C. Grunwald, Jr., Daniel M. Ketcha, Eugene Hern, David R. Cool, and Thomas L. Brown
Journal of Cell Death , 2012, DOI: 10.4137/JCD.S4455
Abstract: The broad-spectrum apoptosis (caspase) inhibitor, Q-VD-OPh, has been shown to have no side effects and is effective at a much lower concentration than other FMK-type caspase inhibitors. However, an appropriate negative control to use with this inhibi- tor has not been available. In this study, we developed and analyzed a new compound, based on the Q-VD-OPh backbone, which acts as a cognate negative control. To create the negative control, we substituted a glutamate residue for the aspartate residue to create Q-VE-OPh, thereby retaining the identical charge and molecular properties with only the addition of an extra –CH2 group. The purity and quality were assessed by ion trap mass spectrometry and verified by nuclear magnetic resonance. We determined the effectiveness of Q-VE-OPh, in comparison to Q-VD-OPh, to prevent DNA fragmentation in human Jurkat T leukemia cells that were induced to undergo apoptosis. DNA fragmentation was analyzed by agarose gel electrophoresis for the presence of DNA laddering, the hallmark indicator of apoptosis. Our results indicate that apoptosis was potently inhibited by Q-VD-OPh. In stark contrast, Q-VE-OPh did not inhibit apoptosis at a similar dose but required at least 20 times greater concentration than Q-VD-OPh to have any inhibitory effect. Western blot analysis showed that Q-VE-OPh was similarly less effective at inhibiting the activation of the extrinsic (caspase 8) and intrinsic (caspase 9) initiator caspases. Cell proliferation and viability studies further demonstrate that Q-VE-OPh is non-toxic, even at high concentration. Our data indicate that the specificity, effectiveness, and absence of toxicity of Q-VE-OPh provides the appropriate and superior negative control for in vitro and in vivo studies when analyzing the effects of o-phenoxy caspase inhibitors.
Genome-Targeted Drug Design: Understanding the Netropsin-DNA Interaction
Ya-Yin Fang, Vernon R. Morris, Guy M. Lingani, Eric C. LongWilliam M. Southerland
The Open Conference Proceedings Journal , 2010, DOI: 10.2174/2210289201001010157]
Abstract: Knowledge of the sequence of the human genome has provided significant opportunities to exploit DNA as a target in the rational design of therapeutic agents. Among agents that target DNA, netropsin exhibits a strong preference for binding A/T rich regions. In order to investigate the key factors responsible for DNA recognition and binding by netropsin, molecular dynamics simulations were carried out on a DNA-netropsin complex in which two netropsin molecules are bound to each AATT site of the 16-mer d(CTTAATTCGAATTAAG)2. In this complex, the two netropsins are bound to the DNA minor groove in a head-to-head orientation with the guanidinium-termini of both netropsins pointed toward the center of the DNA. Despite their identical environments, molecular dynamics simulations showed that the two netropsins exhibited differences in their respective RMS behaviors, binding energies, minor groove width fluctuations, and rotations of their structural planes. These observations suggest that DNA recognition and binding by small molecules may be governed by mechanism(s) that are much more complex than initially anticipated and may represent unexpected challenges in genome-targeted drug design.
Models for Improving Software System Size Estimates during Development  [PDF]
William W. AGRESTI, William M. EVANCO, William M. THOMAS
Journal of Software Engineering and Applications (JSEA) , 2010, DOI: 10.4236/jsea.2010.31001
Abstract: This paper addresses the challenge of estimating eventual software system size during a development project. The ap-proach is to build a family of estimation models that use information about architectural design characteristics of the evolving software product as leading indicators of system size. Four models were developed to provide an increasingly accurate size estimate throughout the design process. Multivariate regression analyses were conducted using 21 Ada subsystems, totaling 183,000 lines of code. The models explain from 47% of the variation in delivered software size early in the design phase, to 89% late in the design phase.
Phosphorylation of HIV-1 Tat by CDK2 in HIV-1 transcription
Tatyana Ammosova, Reem Berro, Marina Jerebtsova, Angela Jackson, Sharroya Charles, Zachary Klase, William Southerland, Victor R Gordeuk, Fatah Kashanchi, Sergei Nekhai
Retrovirology , 2006, DOI: 10.1186/1742-4690-3-78
Abstract: We analyzed HIV-1 Tat phosphorylation by CDK2 in vitro and identified Ser16 and Ser46 residues of Tat as potential phosphorylation sites. Tat was phosphorylated in HeLa cells infected with Tat-expressing adenovirus and metabolically labeled with 32P. CDK2-specific siRNA reduced the amount and the activity of cellular CDK2 and significantly decreased phosphorylation of Tat. Tat co-migrated with CDK2 on glycerol gradient and co-immunoprecipitated with CDK2 from the cellular extracts. Tat was phosphorylated on serine residues in vivo, and mutations of Ser16 and Ser46 residues of Tat reduced Tat phosphorylation in vivo. Mutation of Ser16 and Ser46 residues of Tat reduced HIV-1 transcription in transiently transfected cells. The mutations of Tat also inhibited HIV-1 viral replication and Tat phosphorylation in the context of the integrated HIV-1 provirus. Analysis of physiological importance of the S16QP(K/R)19 and S46YGR49 sequences of Tat showed that Ser16 and Ser46 and R49 residues are highly conserved whereas mutation of the (K/R)19 residue correlated with non-progression of HIV-1 disease.Our results indicate for the first time that Tat is phosphorylated in vivo; Tat phosphorylation is likely to be mediated by CDK2; and phosphorylation of Tat is important for HIV-1 transcription.The human immunodeficiency virus type 1 (HIV-1) requires host cell factors for all steps of the viral replication [1,2]. Recently, multiple covalent modifications of viral proteins that regulate virus-host protein interactions have been described, such as phosphorylation, acetylation and ubiquitination. Phosphorylation has been reported for almost all HIV-1 accessory proteins, including Vpu [3], Vpr [4], Vif [5], Nef [6], and Rev [7]. Transcription of HIV-1 viral genes is induced by a viral transactivator protein (Tat) [1,2]. The activation domain of Tat (amino acids 1–48) interacts with host cell factors, whereas the positively charged RNA-binding domain (amino acids 49–57) interacts with HI
Using the AREA Approach to Create Successful Writers  [PDF]
William M. Yerger
Creative Education (CE) , 2012, DOI: 10.4236/ce.2012.326127
Abstract: The high stakes assessments that states are now administering use a rubric where not only is a correct response required by students, but also a justification or rationale for that response is needed for a higher score on the item. The AREA approach discussed in this article is an excellent strategy that both students and teachers can successfully employ in answering questions either in writing or in public speaking. It is a clear, straightforward way of responding to a question with assurance that the response was developed in a thorough and organized manner.
Magnetic order in quasi-two-dimensional molecular magnets investigated with muon-spin relaxation
Andrew J. Steele,Tom Lancaster,Stephen J. Blundell,Peter J. Baker,Francis L. Pratt,Chris Baines,Marianne M. Conner,Heather I. Southerland,Jamie L. Manson,John A. Schlueter
Physics , 2011, DOI: 10.1103/PhysRevB.84.064412
Abstract: We present the results of a muon-spin relaxation (muSR) investigation into magnetic ordering in several families of layered quasi-two-dimensional molecular antiferromagnets based on transition metal ions such as S=1/2 Cu2+ bridged with organic ligands such as pyrazine. In many of these materials magnetic ordering is difficult to detect with conventional magnetic probes. In contrast, muSR allows us to identify ordering temperatures and study the critical behavior close to T_N . Combining this with measurements of in-plane magnetic exchange J and predictions from quantum Monte Carlo simulations we may assess the degree of isolation of the 2D layers through estimates of the effective inter-layer exchange coupling and in-layer correlation lengths at T_N . We also identify the likely metal-ion moment sizes and muon stopping sites in these materials, based on probabilistic analysis of the magnetic structures and of muon-fluorine dipole-dipole coupling in fluorinated materials.
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