Calculation of resonances and product state distributions for the unimolecular dissociation of H2S

Resonance phenomena associated with the unimolecular dissociation of H2S --> SH + H have been investigated quantum mechanically by the Lanczos homogeneous filter diagonalization method using a newly developed potential energy surface (J. Chem. Phys. 2001, 114, 320). Resonance energies, widths (rates), and product state distributions have been obtained. Both dissociation rates and product state distributions of SH show, strong fluctuations, indicating that the dissociation of H2S is essentially irregular. Statistical analysis of neighboring level spacing and width distributions also confirms this behavior. The dissociation rates and product state distributions are compared to the predictions of quantum phase space theory.

Theoretical investigations of the bulk modulus in the tetra-cubic transition of PbTiO3 material

Resulting from ion displacement in a solid under pressure, piezoelectricity is an electrical polarization that can be observed in perovskite-type electronic ceramics, such as PbTiO3, which present cubic and tetragonal symmetries at different pressures. The transition between these crystalline phases is determined theoretically through the bulk modulus from the relationship between material energy and volume. However, the change in the material molecular structure is responsible for the piezoelectric effect. In this study, density functional theory calculations using the Becke 3-Parameter-Lee-Yang-Parr hybrid functional were employed to investigate the structure and properties associated with the transition state of the tetragonal-cubic phase change in PbTiO3 material.

Stereoselective synthesis of substituted hexahydro-3a,4a-diazacyclopentaphenanthren-4-ones and aminoferrocenes

This thesis explored the development of several methodologies for the stereoselective construction of ligand frameworks and some of their applications. The first segment concerns the application of an enantioselective lithiation at an Sp3_ hybridized position adjacent to nitrogen by means of the widely used and typically highly effective enantioselective lithiation with ( -)-sparteine. This investigation was intended to develop a method to install chirality into a system that would be converted into a family of diaminoylidenes for use as phosphine mimics in transition metal catalysis or as nucleophilic reagents. Molecular modeling of the system revealed some key interactions between the substrate and (-)-sparteine that provided general insight into the diamine's mode of action and should lend some predictive value to its future applications. The second portion focuses on the development of methods to access 1,2- disubstituted aminoferrocenes, an underexplored class of metallocenes possessing planar chirality. Two routes were examined involving a diastereoselective and an enantioselective pathway, where the latter method made use of the first BF3-mediated lithiation-substitution to install planar chirality. Key derivatives such as 1,2- aminophosphines, made readily accessible by the new route, were evaluated as ligands for Pd(II), Pt(II) and Ir(I). These complexes show activity in a number of transformations with both achiral and prochiral substrates. Optimization experiments were conducted to prepare enantiomerically enriched 2-substituted-I-aminoferrocenes by direct asymmetric lithiation of BF3-coordinated tertiary aminoferrocenes. A predictive computational model describing the transition state of this reaction was developed in collaboration with Professor Travis Dudding's group (Department of Chemistry, Brock University). The predicted stereochemistry of the process was confirmed by single-crystal X-ray analysis of a 2-phosphino-l-dimethylaminoferrocene derivative. Enantiomerically pure samples of the aminophosphine ligands derived from this new process have given promising preliminary results in the enantioselective hydrogenation of prochiral alkenes and warrant further stUdy in metal-mediated catalysis.

Femtosecond real-time probing of reactions. 12. Vectorial dynamics of transition states

Femtosecond time-resolved techniques with KETOF (kinetic energy time-of-flight) detection in a molecular beam are developed for studies of the vectorial dynamics of transition states. Application to the dissociation reaction of IHgI is presented. For this system, the complex [I---Hg---I](++)* is unstable and, through the symmetric and asymmetric stretch motions, yields different product fragments: [I---Hg---I](++)* -> HgI(X^2/sigma^+) + I(^2P_3/2) [or I*(^2P_l/2)] (1a); [I---Hg---I](++)* -> Hg(^1S_0) + I(^2P_3/2) + I(^2P_3/2) [or I* (^2P_1/2)] (1 b). These two channels, (1a) and (1b), lead to different kinetic energy distributions in the products. It is shown that the motion of the wave packet in the transition-state region can be observed by MPI mass detection; the transient time ranges from 120 to 300 fs depending on the available energy. With polarized pulses, the vectorial properties (transition moments alignment relative to recoil direction) are studied for fragment separations on the femtosecond time scale. The results indicate the nature of the structure (symmetry properties) and the correlation to final products. For 311-nm excitation, no evidence of crossing between the I and I* potentials is found at the internuclear separations studied. (Results for 287-nm excitation are also presented.) Molecular dynamics simulations and studies by laser-induced fluorescence support these findings.

A potential energy surface for the ground state of formaldehyde, H2CO(1A1)

A model potential energy function for the ground state of H2CO has been derived which covers the whole space of the six internal coordinates. This potential reproduces the experimental energy, geometry and quadratic force field of formaldehyde, and dissociates correctly to all possible atom, diatom and triatom fragments. Thus there are good reasons for believing it to be close to the true potential energy surface except in regions where both hydrogen atoms are close to the oxygen. It leads to the prediction that there should be a metastable singlet hydroxycarbene HCOH which has a planar trans structure and an energy of 2•31 eV above that of equilibrium formaldehyde. The reaction path for dissociation into H2 + CO is predicted to pass through a low symmetry transition state with an activation energy of 4•8 eV. Both of these predictions are in good agreement with recently published ab initio calculations.

Capturing Transition Paths and Transition States for Conformational Rearrangements in the Ribosome

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Insights into Phosphate Cooperativity and Influence of Substrate Modifications on Binding and Catalysis of Hexameric Purine Nucleoside Phosphorylases

The hexameric purine nucleoside phosphorylase from Bacillus subtilis (BsPNP233) displays great potential to produce nucleoside analogues in industry and can be exploited in the development of new anti-tumor gene therapies. In order to provide structural basis for enzyme and substrates rational optimization, aiming at those applications, the present work shows a thorough and detailed structural description of the binding mode of substrates and nucleoside analogues to the active site of the hexameric BsPNP233. Here we report the crystal structure of BsPNP233 in the apo form and in complex with 11 ligands, including clinically relevant compounds. The crystal structure of six ligands (adenine, 2'deoxyguanosine, aciclovir, ganciclovir, 8-bromoguanosine, 6-chloroguanosine) in complex with a hexameric PNP are presented for the first time. Our data showed that free bases adopt alternative conformations in the BsPNP233 active site and indicated that binding of the co-substrate (2'deoxy) ribose 1-phosphate might contribute for stabilizing the bases in a favorable orientation for catalysis. The BsPNP233-adenosine complex revealed that a hydrogen bond between the 5' hydroxyl group of adenosine and Arg(43*) side chain contributes for the ribosyl radical to adopt an unusual C3'-endo conformation. The structures with 6-chloroguanosine and 8-bromoguanosine pointed out that the Cl-6 and Br-8 substrate modifications seem to be detrimental for catalysis and can be explored in the design of inhibitors for hexameric PNPs from pathogens. Our data also corroborated the competitive inhibition mechanism of hexameric PNPs by tubercidin and suggested that the acyclic nucleoside ganciclovir is a better inhibitor for hexameric PNPs than aciclovir. Furthermore, comparative structural analyses indicated that the replacement of Ser(90) by a threonine in the B. cereus hexameric adenosine phosphorylase (Thr(91)) is responsible for the lack of negative cooperativity of phosphate binding in this enzyme.

X-ray diffraction and theoretical investigation of the Gedunin crystal structure

The Gedunin compound (C28H34O6) is a natural product extracted from Trichilia pallida that has shown a wide activity. The crystallographic structure shows two conformers in the asymmetric unit, which differ in a rotation of the furan group. To understand this molecular arrangement, the density functional calculations. Molecular Electrostatic Potential (MEP) and thermodynamic function calculation have been performed at the B3LYP/6-311++g(d,p) level. Both conformers were optimized and the agreement with the experimental structure was very good, making possible further theoretical analysis of the structure. The inter-conversion between two conformers depends on the energy barrier. This process is studied in the vacuum and shows two transition states with a low energetic barrier for a potential energy curve scanning rigid around furan group: 4.37 kcal/mol and 16.52 kcal/mol. As the first transition state has a notably lower energetic barrier, the preferred inter-conversion pathway between the conformers involves the first rather than the second transition state. Understanding this transition state in detail led us to perform its optimization, showing an energetic barrier around 3.66 kcal/mol. The negative free energy and low enthalpy confirm that the process is spontaneous and exothermic. The results show that this requirement makes the existence of the two conformers in the asymmetric unit possible. The structure of molecules in the asymmetric unit is better understood when the MEP is used on the interaction between molecules. For Gedunin, both molecules have shown MEP with well-defined regions, and this behavior contributes to the observed link between molecules and for the negative regions complementing positive regions of another molecule. (C) 2011 Elsevier B.V. All rights reserved.

Design and synthesis of novel non peptidomimtic beta-secretase inhibitors in the treatment of Alzheimer's disease

The aspartic protease BACE1 (β-amyloid precursor protein cleaving enzyme, β-secretase) is recognized as one of the most promising targets in the treatment of Alzheimer's disease (AD). The accumulation of β-amyloid peptide (Aβ) in the brain is a major factor in the pathogenesis of AD. Aβ is formed by initial cleavage of β-amyloid precursor protein (APP) by β-secretase, therefore BACE1 inhibition represents one of the therapeutic approaches to control progression of AD, by preventing the abnormal generation of Aβ. For this reason, in the last decade, many research efforts have focused at the identification of new BACE1 inhibitors as drug candidates. Generally, BACE1 inhibitors are grouped into two families: substrate-based inhibitors, designed as peptidomimetic inhibitors, and non-peptidomimetic ones. The research on non-peptidomimetic small molecules BACE1 inhibitors remains the most interesting approach, since these compounds hold an improved bioavailability after systemic administration, due to a good blood-brain barrier permeability in comparison to peptidomimetic inhibitors. Very recently, our research group discovered a new promising lead compound for the treatment of AD, named lipocrine, a hybrid derivative between lipoic acid and the AChE inhibitor (AChEI) tacrine, characterized by a tetrahydroacridinic moiety. Lipocrine is one of the first compounds able to inhibit the catalytic activity of AChE and AChE-induced amyloid-β aggregation and to protect against reactive oxygen species. Due to this interesting profile, lipocrine was also evaluated for BACE1 inhibitory activity, resulting in a potent lead compound for BACE1 inhibition. Starting from this interesting profile, a series of tetrahydroacridine analogues were synthesised varying the chain length between the two fragments. Moreover, following the approach of combining in a single molecule two different pharmacophores, we designed and synthesised different compounds bearing the moieties of known AChEIs (rivastigmine and caproctamine) coupled with lipoic acid, since it was shown that dithiolane group is an important structural feature of lipocrine for the optimal inhibition of BACE1. All the tetrahydroacridines, rivastigmine and caproctamine-based compounds, were evaluated for BACE1 inhibitory activity in a FRET (fluorescence resonance energy transfer) enzymatic assay (test A). With the aim to enhancing the biological activity of the lead compound, we applied the molecular simplification approach to design and synthesize novel heterocyclic compounds related to lipocrine, in which the tetrahydroacridine moiety was replaced by 4-amino-quinoline or 4-amino-quinazoline rings. All the synthesized compounds were also evaluated in a modified FRET enzymatic assay (test B), changing the fluorescent substrate for enzymatic BACE1 cleavage. This test method guided deep structure-activity relationships for BACE1 inhibition on the most promising quinazoline-based derivatives. By varying the substituent on the 2-position of the quinazoline ring and by replacing the lipoic acid residue in lateral chain with different moieties (i.e. trans-ferulic acid, a known antioxidant molecule), a series of quinazoline derivatives were obtained. In order to confirm inhibitory activity of the most active compounds, they were evaluated with a third FRET assay (test C) which, surprisingly, did not confirm the previous good activity profiles. An evaluation study of kinetic parameters of the three assays revealed that method C is endowed with the best specificity and enzymatic efficiency. Biological evaluation of the modified 2,4-diamino-quinazoline derivatives measured through the method C, allow to obtain a new lead compound bearing the trans-ferulic acid residue coupled to 2,4-diamino-quinazoline core endowed with a good BACE1 inhibitory activity (IC50 = 0.8 mM). We reported on the variability of the results in the three different FRET assays that are known to have some disadvantages in term of interference rates that are strongly dependent on compound properties. The observed results variability could be also ascribed to different enzyme origin, varied substrate and different fluorescent groups. The inhibitors should be tested on a parallel screening in order to have a more reliable data prior to be tested into cellular assay. With this aim, preliminary cellular BACE1 inhibition assay carried out on lipocrine confirmed a good cellular activity profile (EC50 = 3.7 mM) strengthening the idea to find a small molecule non-peptidomimetic compound as BACE1 inhibitor. In conclusion, the present study allowed to identify a new lead compound endowed with BACE1 inhibitory activity in submicromolar range. Further lead optimization to the obtained derivative is needed in order to obtain a more potent and a selective BACE1 inhibitor based on 2,4-diamino-quinazoline scaffold. A side project related to the synthesis of novel enzymatic inhibitors of BACE1 in order to explore the pseudopeptidic transition-state isosteres chemistry was carried out during research stage at Università de Montrèal (Canada) in Hanessian's group. The aim of this work has been the synthesis of the δ-aminocyclohexane carboxylic acid motif with stereochemically defined substitution to incorporating such a constrained core in potential BACE1 inhibitors. This fragment, endowed with reduced peptidic character, is not known in the context of peptidomimetic design. In particular, we envisioned an alternative route based on an organocatalytic asymmetric conjugate addition of nitroalkanes to cyclohexenone in presence of D-proline and trans-2,5-dimethylpiperazine. The enantioenriched obtained 3-(α-nitroalkyl)-cyclohexanones were further functionalized to give the corresponding δ-nitroalkyl cyclohexane carboxylic acids. These intermediates were elaborated to the target structures 3-(α-aminoalkyl)-1-cyclohexane carboxylic acids in a new readily accessible way.

Hydrogen bonding of nucleotide base pairs: Application of the PM3 method

The ability of the pm3 semiempirical quantum mechanical method to reproduce hydrogen bonding in nucleotide base pairs was assessed. Results of pm3 calculations on the nucleotides 2′-deoxyadenosine 5′-monophosphate (pdA), 2′-deoxyguanosine 5′-monophosphate (pdG), 2′-deoxycytidine 5′-monophosphate (pdC), and 2′-deoxythymidine 5′-monophosphate (pdT) and the base pairs pdA–pdT, pdG–pdC, and pdG(syn)–pdC are presented and discussed. The pm3 method is the first of the parameterized nddo quantum mechanical models with any ability to reproduce hydrogen bonding between nucleotide base pairs. Intermolecular hydrogen bond lengths between nucleotides displaying Watson–Crick base pairing are 0.1–0.2 Å less than experimental results. Nucleotide bond distances, bond angles, and torsion angles about the glycosyl bond (χ), the C4′C5′ bond (γ), and the C5′O5′ bond (β) agree with experimental results. There are many possible conformations of nucleotides. pm3 calculations reveal that many of the most stable conformations are stabilized by intramolecular CHO hydrogen bonds. These interactions disrupt the usual sugar puckering. The stacking interactions of a dT–pdA duplex are examined at different levels of gradient optimization. The intramolecular hydrogen bonds found in the nucleotide base pairs disappear in the duplex, as a result of the additional constraints on the phosphate group when part of a DNA backbone. Sugar puckering is reproduced by the pm3 method for the four bases in the dT–pdA duplex. pm3 underestimates the attractive stacking interactions of base pairs in a B-DNA helical conformation. The performance of the pm3 method implemented in SPARTAN is contrasted with that implemented in MOPAC. At present, accurate ab initio calculations are too timeconsuming to be of practical use, and molecular mechanics methods cannot be used to determine quantum mechanical properties such as reaction-path calculations, transition-state structures, and activation energies. The pm3 method should be used with extreme caution for examination of small DNA systems. Future parameterizations of semiempirical methods should incorporate base stacking interactions into the parameterization data set to enhance the ability of these methods.

Myanmar's two decades of partial transition to a market economy : a negative legacy for the new government

Despite more than two decades of transition from a centrally planned to a market-oriented economy, Myanmar’s economic transition is still only partly complete. The government’s initial strategy for dealing with the swelling deficits of the state economic enterprises (SEEs) was to put them under direct control in order to scrutinize their expenditures. This policy change postponed restructuring and exacerbated the soft budget constraint problem of the SEEs. While the installation of a new government in March 2011 has increased prospects for economic development, sustainable growth still requires full-scale structural reform of the SEEs and institutional infrastructure building. Myanmar can learn from the gradual approaches to economic transition in China and Vietnam, where partial reforms weakened further impetus for reforms.

Wide bandwidth envelope trackers with reduced switching frequency for RF power amplifier

El requerimiento de proveer alta frecuencia de datos en los modernos sistema de comunicación inalámbricos resulta en complejas señales moduladas de radio-frequencia (RF) con un gran ancho de banda y alto ratio pico-promedio (PAPR). Para garantizar la linealidad del comportamiento, los amplificadores lineales de potencia comunes funcionan típicamente entre 4 y 10 dB de back-o_ desde la máxima potencia de salida, ocasionando una baja eficiencia del sistema. La eliminación y restauración de la evolvente (EER) y el seguimiento de la evolvente (ET) son dos prometedoras técnicas para resolver el problema de la eficiencia. Tanto en EER como en ET, es complicado diseñar un amplificador de potencia que sea eficiente para señales de RF de alto ancho de banda y alto PAPR. Una propuesta común para los amplificadores de potencia es incluir un convertidor de potencia de muy alta eficiencia operando a frecuencias más altas que el ancho de banda de la señal RF. En este caso, la potencia perdida del convertidor ocasionado por la alta frecuencia desaconseja su práctica cuando el ancho de banda es muy alto. La solución a este problema es el enfoque de esta disertación que presenta dos arquitecturas de amplificador evolvente: convertidor híbrido-serie con una técnica de evolvente lenta y un convertidor multinivel basado en un convertidor reductor multifase con control de tiempo mínimo. En la primera arquitectura, una topología híbrida está compuesta de una convertidor reductor conmutado y un regulador lineal en serie que trabajan juntos para ajustar la tensión de salida para seguir a la evolvente con precisión. Un algoritmo de generación de una evolvente lenta crea una forma de onda con una pendiente limitada que es menor que la pendiente máxima de la evolvente original. La salida del convertidor reductor sigue esa forma de onda en vez de la evolvente original usando una menor frecuencia de conmutación, porque la forma de onda no sólo tiene una pendiente reducida sino también un menor ancho de banda. De esta forma, el regulador lineal se usa para filtrar la forma de onda tiene una pérdida de potencia adicional. Dependiendo de cuánto se puede reducir la pendiente de la evolvente para producir la forma de onda, existe un trade-off entre la pérdida de potencia del convertidor reductor relacionada con la frecuencia de conmutación y el regulador lineal. El punto óptimo referido a la menor pérdida de potencia total del amplificador de evolvente es capaz de identificarse con la ayuda de modelo preciso de pérdidas que es una combinación de modelos comportamentales y analíticos de pérdidas. Además, se analiza el efecto en la respuesta del filtro de salida del convertidor reductor. Un filtro de dampeo paralelo extra es necesario para eliminar la oscilación resonante del filtro de salida porque el convertidor reductor opera en lazo abierto. La segunda arquitectura es un amplificador de evolvente de seguimiento de tensión multinivel. Al contrario que los convertidores que usan multi-fuentes, un convertidor reductor multifase se emplea para generar la tensión multinivel. En régimen permanente, el convertidor reductor opera en puntos del ciclo de trabajo con cancelación completa del rizado. El número de niveles de tensión es igual al número de fases de acuerdo a las características del entrelazamiento del convertidor reductor. En la transición, un control de tiempo mínimo (MTC) para convertidores multifase es novedosamente propuesto y desarrollado para cambiar la tensión de salida del convertidor reductor entre diferentes niveles. A diferencia de controles convencionales de tiempo mínimo para convertidores multifase con inductancia equivalente, el propuesto MTC considera el rizado de corriente por cada fase basado en un desfase fijo que resulta en diferentes esquemas de control entre las fases. La ventaja de este control es que todas las corrientes vuelven a su fase en régimen permanente después de la transición para que la siguiente transición pueda empezar muy pronto, lo que es muy favorable para la aplicación de seguimiento de tensión multinivel. Además, el control es independiente de la carga y no es afectado por corrientes de fase desbalanceadas. Al igual que en la primera arquitectura, hay una etapa lineal con la misma función, conectada en serie con el convertidor reductor multifase. Dado que tanto el régimen permanente como el estado de transición del convertidor no están fuertemente relacionados con la frecuencia de conmutación, la frecuencia de conmutación puede ser reducida para el alto ancho de banda de la evolvente, la cual es la principal consideración de esta arquitectura. La optimización de la segunda arquitectura para más alto anchos de banda de la evolvente es presentada incluyendo el diseño del filtro de salida, la frecuencia de conmutación y el número de fases. El área de diseño del filtro está restringido por la transición rápida y el mínimo pulso del hardware. La rápida transición necesita un filtro pequeño pero la limitación del pulso mínimo del hardware lleva el diseño en el sentido contrario. La frecuencia de conmutación del convertidor afecta principalmente a la limitación del mínimo pulso y a las pérdidas de potencia. Con una menor frecuencia de conmutación, el ancho de pulso en la transición es más pequeño. El número de fases relativo a la aplicación específica puede ser optimizado en términos de la eficiencia global. Otro aspecto de la optimización es mejorar la estrategia de control. La transición permite seguir algunas partes de la evolvente que son más rápidas de lo que el hardware puede soportar al precio de complejidad. El nuevo método de sincronización de la transición incrementa la frecuencia de la transición, permitiendo que la tensión multinivel esté más cerca de la evolvente. Ambas estrategias permiten que el convertidor pueda seguir una evolvente con un ancho de banda más alto que la limitación de la etapa de potencia. El modelo de pérdidas del amplificador de evolvente se ha detallado y validado mediante medidas. El mecanismo de pérdidas de potencia del convertidor reductor tiene que incluir las transiciones en tiempo real, lo cual es diferente del clásico modelos de pérdidas de un convertidor reductor síncrono. Este modelo estima la eficiencia del sistema y juega un papel muy importante en el proceso de optimización. Finalmente, la segunda arquitectura del amplificador de evolvente se integra con el amplificador de clase F. La medida del sistema EER prueba el ahorro de energía con el amplificador de evolvente propuesto sin perjudicar la linealidad del sistema. ABSTRACT The requirement of delivering high data rates in modern wireless communication systems results in complex modulated RF signals with wide bandwidth and high peak-to-average ratio (PAPR). In order to guarantee the linearity performance, the conventional linear power amplifiers typically work at 4 to 10 dB back-off from the maximum output power, leading to low system efficiency. The envelope elimination and restoration (EER) and envelope tracking (ET) are two promising techniques to overcome the efficiency problem. In both EER and ET, it is challenging to design efficient envelope amplifier for wide bandwidth and high PAPR RF signals. An usual approach for envelope amplifier includes a high-efficiency switching power converter operating at a frequency higher than the RF signal's bandwidth. In this case, the power loss of converter caused by high switching operation becomes unbearable for system efficiency when signal bandwidth is very wide. The solution of this problem is the focus of this dissertation that presents two architectures of envelope amplifier: a hybrid series converter with slow-envelope technique and a multilevel converter based on a multiphase buck converter with the minimum time control. In the first architecture, a hybrid topology is composed of a switched buck converter and a linear regulator in series that work together to adjust the output voltage to track the envelope with accuracy. A slow envelope generation algorithm yields a waveform with limited slew rate that is lower than the maximum slew rate of the original envelope. The buck converter's output follows this waveform instead of the original envelope using lower switching frequency, because the waveform has not only reduced slew rate but also reduced bandwidth. In this way, the linear regulator used to filter the waveform has additional power loss. Depending on how much reduction of the slew rate of envelope in order to obtain that waveform, there is a trade-off between the power loss of buck converter related to the switching frequency and the power loss of linear regulator. The optimal point referring to the lowest total power loss of this envelope amplifier is identified with the help of a precise power loss model that is a combination of behavioral and analytic loss model. In addition, the output filter's effect on the response is analyzed. An extra parallel damping filter is needed to eliminate the resonant oscillation of output filter L and C, because the buck converter operates in open loop. The second architecture is a multilevel voltage tracking envelope amplifier. Unlike the converters using multi-sources, a multiphase buck converter is employed to generate the multilevel voltage. In the steady state, the buck converter operates at complete ripple cancellation points of duty cycle. The number of the voltage levels is equal to the number of phases according the characteristics of interleaved buck converter. In the transition, a minimum time control (MTC) for multiphase converter is originally proposed and developed for changing the output voltage of buck converter between different levels. As opposed to conventional minimum time control for multiphase converter with equivalent inductance, the proposed MTC considers the current ripple of each phase based on the fixed phase shift resulting in different control schemes among the phases. The advantage of this control is that all the phase current return to the steady state after the transition so that the next transition can be triggered very soon, which is very favorable for the application of multilevel voltage tracking. Besides, the control is independent on the load condition and not affected by the unbalance of phase current. Like the first architecture, there is also a linear stage with the same function, connected in series with the multiphase buck converter. Since both steady state and transition state of the converter are not strongly related to the switching frequency, it can be reduced for wide bandwidth envelope which is the main consideration of this architecture. The optimization of the second architecture for wider bandwidth envelope is presented including the output filter design, switching frequency and the number of phases. The filter design area is restrained by fast transition and the minimum pulse of hardware. The fast transition needs small filter but the minimum pulse of hardware limitation pushes the filter in opposite way. The converter switching frequency mainly affects the minimum pulse limitation and the power loss. With lower switching frequency, the pulse width in the transition is smaller. The number of phases related to specific application can be optimized in terms of overall efficiency. Another aspect of optimization is improving control strategy. Transition shift allows tracking some parts of envelope that are faster than the hardware can support at the price of complexity. The new transition synchronization method increases the frequency of transition, allowing the multilevel voltage to be closer to the envelope. Both control strategies push the converter to track wider bandwidth envelope than the limitation of power stage. The power loss model of envelope amplifier is detailed and validated by measurements. The power loss mechanism of buck converter has to include the transitions in real time operation, which is different from classical power loss model of synchronous buck converter. This model estimates the system efficiency and play a very important role in optimization process. Finally, the second envelope amplifier architecture is integrated with a Class F amplifier. EER system measurement proves the power saving with the proposed envelope amplifier without disrupting the linearity performance.

Yeast chorismate mutase in the R state: Simulations of the active site

The isomerization of chorismate to prephenate by chorismate mutase in the biosynthetic pathway that forms Tyr and Phe involves C5—O (ether) bond cleavage and C1—C9 bond formation in a Claisen rearrangement. Development of negative charge on the ether oxygen, stabilized by Lys-168 and Glu-246, is inferred from the structure of a complex with a transition state analogue (TSA) and from the pH-rate profile of the enzyme and the E246Q mutant. These studies imply a protonated Glu-246 well above pH 7. Here, several 500-ps molecular dynamics simulations test the stability of enzyme–TSA complexes by using a solvated system with stochastic boundary conditions. The simulated systems are (i) protonated Glu-246 (stable), (ii) deprotonated Glu-246 (unstable), (iii) deprotonated Glu-246 plus one H2O between Glu-246 and the ether oxygen (unstable), (iv) the E246Q mutant (stable), and (v) addition of OH− between protonated Glu-246 and the ether oxygen. In (v), a local conformational change of Lys-168 displaced the OH− into the solvent region, suggesting a possible rate-determining step that precedes the catalytic step. In a 500-ps simulation of the enzyme complexed with the reactant chorismate or the product prephenate, no water molecule remained near the oxygen of the ligand. Calculations using the linearized Poisson–Boltzmann equation show that the effective pKa of Glu-246 is shifted from 5.8 to 8.1 as the negative charge on the ether oxygen of the TSA is changed from −0.56 electron to −0.9 electron. Altogether, these results support retention of a proton on Glu-246 to high pH and the absence of a water molecule in the catalytic steps.

From snapshot to movie: φ analysis of protein folding transition states taken one step further

Kinetic anomalies in protein folding can result from changes of the kinetic ground states (D, I, and N), changes of the protein folding transition state, or both. The 102-residue protein U1A has a symmetrically curved chevron plot which seems to result mainly from changes of the transition state. At low concentrations of denaturant the transition state occurs early in the folding reaction, whereas at high denaturant concentration it moves close to the native structure. In this study we use this movement to follow continuously the formation and growth of U1A's folding nucleus by φ analysis. Although U1A's transition state structure is generally delocalized and displays a typical nucleation–condensation pattern, we can still resolve a sequence of folding events. However, these events are sufficiently coupled to start almost simultaneously throughout the transition state structure.

Limited internal friction in the rate-limiting step of a two-state protein folding reaction

Small, single-domain proteins typically fold via a compact transition-state ensemble in a process well fitted by a simple, two-state model. To characterize the rate-limiting conformational changes that underlie two-state folding, we have investigated experimentally the effects of changing solvent viscosity on the refolding of the IgG binding domain of protein L. In conjunction with numerical simulations, our results indicate that the rate-limiting conformational changes of the folding of this domain are strongly coupled to solvent viscosity and lack any significant “internal friction” arising from intrachain collisions. When compared with the previously determined solvent viscosity dependencies of other, more restricted conformational changes, our results suggest that the rate-limiting folding transition involves conformational fluctuations that displace considerable amounts of solvent. Reconciling evidence that the folding transition state ensemble is comprised of highly collapsed species with these and similar, previously reported results should provide a significant constraint for theoretical models of the folding process.