Aeronautical Engineering: A special bibliography, supplement 60

This bibliography lists 284 reports, articles, and other documents introduced into the NASA scientific and technical information system in July 1975

Sensor-based robust incremental three-dimensional guidance law with terminal angle constraint

In this work, a robust incremental three-dimensional (3D) guidance law is proposed considering terminal angle constraint against maneuvering targets. As a stepping stone, the line-of-sight (LOS) tracking error dynamics is employed for the 3D guidance law design. A sliding variable is constructed such that its first-order derivative excludes the relative range in the perturbation, which avoids the unboundedness of system perturbation induced by target maneuvers near collision. A time-varying version of the sliding variable is designed to accelerate convergence of the LOS tracking errors and avoid large initial sliding variables. Then, two guidance laws are derived as a benchmark via the nonlinear dynamic inversion (NDI)-based sliding mode control (NDI-SMC) and NDI-based time-varying sliding mode control (NDI-TVSMC), respectively. To further improve guidance robustness with reduced system perturbation, the sensor-based incremental nonlinear dynamic inversion (INDI) control is used to design the INDI-SMC-based and INDI-TVSMC-based guidance laws. The sensor-based guidance laws exploit the LOS angular acceleration and guidance command output at the latest step, which result in smaller guidance gains to reject the perturbation than the NDI guidance laws. Numerical simulations in various cases and comparison studies are conducted to verify the effectiveness and robustness of the proposed method

Modeling Assemblies and Interactions at the Replication Fork: Sliding Clamps and Clamp Interacting Enzymes

DNA sliding clamps are structurally conservative toroid-shape proteins that encircle and slide along DNA, serving as scaffold for other functional enzymes to act on DNA and ensuring the replication proccessivity, thereby, of fundamental biological significance across domains of life. Mechanistic details and related functional implications concerning clamp opening, interaction between clamp and clamp-interactive proteins, post-translational modification of sliding clamp remain largely elusive due to technical difficulties in single molecule level manipulations and structural studies on large biological complex. Toward the end of providing a unified molecular-level description on clamp loading that would account for all available experimental observations, we calculated the interface binding energy and depicted the residue pair contributions using MM/PBSA and MM/GBSA calculations to compare the different interfaces of sliding clamps, and dissolved the uncertainty in comparative stability of different sliding clamp interfaces. The possible interface breaking pathways were investigated by sampling the opening state of interfaces using SMD simulations. Functioning as a polymerase accessory factor, sliding clamp associates with the dual enzymatic functional polymerase B (PolB) as DNA replication occurs. The massive conformational switch of PolB between replicating and editing mode is recognized for its functional significance but little is understood in the context of the PCNA/PolB/DNA complex. We integrated the structural informations from individual and binary crystal structures, as well as low-resolution structural information and other functional assay results, to build the complex atomistic models in both modes and refine them through atomistic simulations. The transition process was probed using TMD and ENM to reveal the structural characteristics and determinants of the transition. Sliding clamp is also a master coordinator of cellular responses to DNA damage. Efforts with the same methodology were made on human PCNA/FEN1/DNA ternary complex to investigate the reversible associations of FEN1 to PCNA and the conformational switching leading to exchange of repair intermediates. In the third thrust, we modeled the ubiquitin-modified and SUMO-modified PCNA using protein-protein docking and atomic simulation. Alongside with the SAXS data, our results revealed the structural basis for the distinct functional outcomes upon different posttranslational modification of PCNA

Dynamics of protein-drug interactions inferred from structural ensembles and physics-based models

The conformational flexibility of target proteins is a major challenge in understanding and modeling protein-drug interactions. A fundamental issue, yet to be clarified, is whether the observed conformational changes are controlled by the protein, or induced by the inhibitor. While the concept of induced fit has been widely adopted for describing the structural changes that accompany ligand binding, there is growing evidence in support of the dominance of proteins' intrinsic dynamics, which has been evolutionarily optimized to accommodate its functional interactions. The wealth of structural data for target proteins in the presence of different ligands now permits us to make a critical assessment of the balance between these two effects in selecting the bound forms. We focused on three widely studied drug targets, HIV-1 reverse transcriptase, p38 MAP kinase, and cyclin-dependent kinase 2. A total of 292 structures determined for these enzymes in the presence of different inhibitors as well as unbound form permitted us to perform an extensive comparative analysis of the conformational space accessed upon ligand binding, and its relation to the intrinsic dynamics prior to ligand binding as predicted by elastic network model analysis. Further, we analyzed NMR ensembles of ubiquitin and calmodulin representing their microseconds range solution dynamics. Our results show that the ligand selects the conformer that best matches its structural and dynamic properties amongst the conformers intrinsically accessible to the protein in the unliganded form. The results suggest that simple but robust rules encoded in the protein structure play a dominant role in pre-defining the mechanisms of ligand binding, which may be advantageously exploited in designing inhibitors. We apply these lessons to the study of MAP kinase phosphatases (MKPs), which are therapeutically relevant but challenging signaling enzymes. Our study provides insights into the interactions and selectivity of MKP inhibitors and shows how an allosteric inhibition mechanism holds for a recently discovered inhibitor of MKP-3. We also provide evidence for the functional significance of the structure-encoded dynamics of rhodopsin and nicotinic acetylcholine receptor, members of two membrane proteins classes serving as targets for more than 40% of all current FDA approved drugs

Molecular dynamics study of HIV-1 protease inhibitors and their effects on the flap dynamics of the HIV-1 subtype-C (C-SA).

Masters Degree. University of KwaZulu-Natal, Durban.The aspartyl protease human immunodeficiency virus type 1 (HIV-1) is a 99-amino acid-long homodimer responsible for processing the Gag and Gag-Pol polyproteins into functional constituent proteins necessary for development of infectious HIV particles. Of global infections recorded, subSaharan African region is represented by 56 % where nearly 25 million people are living with HIV. South Africa has been shown to carry the heaviest HIV burden in sub-Saharan Africa where the HIV-1 subtype C (C-SA) is the prominent strain. Most of the HIV-1 scientific research has been done specifically for subtype B and this has been highlighted by the weaker binding affinity displayed by the South African HIV-1 subtype C for most of the clinically approved protease inhibitors when compared to the HIV-1 subtype B protease. The two flaps of the HIV-1 PR are very essential in functioning of the enzyme as their conformations control entry of the substrate into the catalytic site of the enzyme and also to release product. It is very important to explore and understand the dynamics of these flaps in binding of different inhibitors with different binding affinities. In addition, studies have highlighted the focus on inhibiting the cleaving function of HIV-1 PR with protease inhibitors (PIs) by competing with the natural substrate for the enzyme’s active or catalytic site and thus rendering its ineffective. It has been shown that in addition to the active site, more regions of the enzyme can be possible targets for inhibition process by developing drugs that can hinder the opening of the flaps or disrupt the stability of the dimer interface. This study involved the use of computational techniques to explore the major contributing factors other than interactions with the binding site, in binding affinity of FDA approved second generation PIs complexed to HIV-1 C-SA PR. In pursuance of this objective, molecular dynamics simulations, binding-free energy calculations and dynamic analyses were utilized. Several distances, different angles between certain residues were all taken into consideration. Our findings do show that apart from binding free-energy calculations, not one single factor but several factors contribute to the binding affinity of protease inhibitors. It is clear from these results that in the development of new HIV-1 drugs, more emphasis should be made in the design of drugs with, not only better binding in the active site but also with better interaction with other regions of the enzyme. Another interesting emphasis drawn from this study is that there is still need for drug development targeting HIV-1 PR C-SA as the currently available drugs were modelled around the inhibition of HIV-1 subtype B

Biomimetic oscillating foil propulsion to enhance underwater vehicle agility and maneuverability

Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the Massachusetts Institute of Technology and the Woods Hole Oceanographic Institution June 2008Inspired by the swimming abilities of marine animals, this thesis presents "Finnegan the RoboTurtle", an autonomous underwater vehicle (AUV) powered entirely by four flapping foils. Biomimetic actuation is shown to produce dramatic improvements in AUV maneuvering at cruising speeds, while simultaneously allowing for agility at low speeds. Using control algorithms linear in the modified Rodrigues parameters to support large angle maneuvers, the vehicle is successfully controlled in banked and twisting turns, exceeding the best reported AUV turning performance by more than a factor of two; a minimum turning radius of 0.7BL, and the ability to avoid walls detected> 1.8BL ahead, are found for cruising speeds of 0.75BL/S, with a maximum heading rate of 400 / S recorded. Observations of "Myrtle", a 250kg Green sea turtle (Chelonia mydas) at the New England Aquarium, are detailed; along with steady swimming, Myrtle is observed performing 1800 level turns and rapidly actuating pitch to control depth and speed. Limb kinematics for the level turning maneuver are replicated by Finnegan, and turning rates comparable to those of the turtle are achieved. Foil kinematics which produce approximately sinusoidal nominal angle of attack trace are shown to improve turning performance by as much as 25%; the effect is achieved despite limited knowledge of the flow field. Finally, tests with a single foil are used to demonstrate that biomimetically inspired inline motion can allow oscillating foils utilizing a power/recovery style stroke to generate as much as 90% of the thrust from a power/power stroke style motion

Aeronautical engineering: A special bibliography with indexes, supplement 80

This bibliography lists 277 reports, articles, and other documents introduced into the NASA scientific and technical information system in January 1977

Clustering of Epigenetic Methylation and Oxidative Damage: Effects on Duplex DNA Solution Structure, Thermodynamic Stability and Local Dynamics

All known living organisms use DNA to store genetic templates used for development, proper function and reproduction. The structural integrity of DNA is therefore of extreme importance and cellular machinery continuously regulates our DNA either through addition of covalent molecules to regulate the transcription of genes or the removal of DNA lesions propagating from the exposure to reactive molecules. One of the most common DNA lesions, 8-oxoguanine (8OG), is a prominent, pro-mutagenic DNA adduct present at a baseline level from consistent generation of reactive oxygen species through oxidative metabolism or at greater concentrations through exposure to ionizing radiation and other toxins. Its mutagenic potential is attributed to its ability in the syn- conformation, to mimic thymine during DNA replication, resulting in a mispair with adenine. In contrast, 5-methylcytosine (5MC), occurs from the covalent addition of a methyl group to a cytosine base by a DNA methyltransferase. 5MC acts as an epigenetic gene regulator, often found densely packed within CpG islands upstream of transcriptionally inactive genes. It can be estimated that each human diploid cell contains hundreds of CpG dinucleotides undergoing active methylation while also harboring 8OG. Previous results obtained by Kasymov et al, showed reduced endonuclease activity by hOGG1 for substrates containing 5MC adjacent and cross strand from 8OG. In addition, the work presented by Maltseva et al, conveyed that the enzymatic methylation rates by maintenance DNA methyltransferases were severely impacted when 8OG is adjacent to the methylation target. These results prompted us to investigate the clustering of these two modifications in greater detail. We present the results of solution NMR structure determination, thermodynamic stability analysis and molecular dynamics simulations on the DNA sequence 5’-d(CGCGAATTCGCG)-3’ with clustered 5MC and 8OG in CpG dinucleotides. NMR spectroscopy and restrained molecular dynamics were used to refine the structure of 11 DNA duplexes containing different methylation and oxidation patterns. The results reveal that 8OG induces local unwinding 5’ to itself and 31P chemical shifts indicate an increase in the BII phosphate backbone conformation 3’ relative to 8OG. Melting temperatures of the duplexes was shown to decrease with the addition of 8OG in all contexts. Surprisingly, the addition of 5MC in two separate instances led to lower Tm values of already oxidized DNA samples. 1D-1H NMR linewidths indicate 8OG increases the base dynamics while incorporation of 5MC leads to a stabilizing effect. Our results indicate that addition of 8OG to a fully-methylated CpG induces a sequence dependent stabilizing effect. Molecular dynamics trajectories were analyzed for BI/BII phosphate conformation populations, conformational flexibility and local dynamics. Comparison of helical geometries and backbone angles indicated that our MD simulations accurately and reliably reproduced our NMR structures within one standard deviation. Principal component analysis was carried out to highlight the most dominant modes of motion for CpG sites with clustered 5MC and 8OG. Particularly, we report significant differences in concerted atomic displacements, with the 8OG:5MC base pair displaying the greatest dynamic effects