Frustration and hydrophobicity interplay in protein folding and protein evolution

A lattice model is used to study mutations and compacting effects on protein folding rates and folding temperature. In the context of protein evolution, we address the question regarding the best scenario for a polypeptide chain to fold: either a fast nonspecific collapse followed by a slow rearrangement to form the native structure or a specific collapse from the unfolded state with the simultaneous formation of the native state. This question is investigated for optimized sequences, whose native state has no frustrated contacts between monomers, and also for mutated sequences, whose native state has some degree of frustration. It is found that the best scenario for folding may depend on the amount of frustration of the native structure. The implication of this result on protein evolution is discussed. (c) 2006 American Institute of Physics.

Probing the kinetics of single molecule protein folding

We propose an approach to integrate the theory, simulations, and experiments in protein-folding kinetics. This is realized by measuring the mean and high-order moments of the first-passage time and its associated distribution. The full kinetics is revealed in the current theoretical framework through these measurements. In the experiments, information about the statistical properties of first-passage times can be obtained from the kinetic folding trajectories of single molecule experiments ( for example, fluorescence). Theoretical/simulation and experimental approaches can be directly related. We study in particular the temperature-varying kinetics to probe the underlying structure of the folding energy landscape. At high temperatures, exponential kinetics is observed; there are multiple parallel kinetic paths leading to the native state. At intermediate temperatures, nonexponential kinetics appears, revealing the nature of the distribution of local traps on the landscape and, as a result, discrete kinetic paths emerge. At very low temperatures, exponential kinetics is again observed; the dynamics on the underlying landscape is dominated by a single barrier. The ratio between first-passage-time moments is proposed to be a good variable to quantitatively probe these kinetic changes. The temperature-dependent kinetics is consistent with the strange kinetics found in folding dynamics experiments. The potential applications of the current results to single-molecule protein folding are discussed.

Pauli nonlocality in heavy-ion rainbow scattering: A further test of the folding model

Nonlocal interactions are an intrinsically quantum phenomenon. In this work we point out that, in the context of heavy ions, such interactions can be studied through the refractive elastic scattering of these systems at intermediate energies. We show that most of the observed energy dependence of the local equivalent bare potential arises from the exchange nonlocality. The nonlocality parameter extracted from the data was found to be very close to the one obtained from folding models. The effective mass of the colliding, heavy-ion, system was found to be close to the nucleon effective mass in nuclear matter.

A linearly-tunable OTA-C sinusoidal oscillator for low-voltage applications

A low-voltage, low-power OTA-C sinusoidal oscillator based on a triode-MOSFET transconductor is here discussed. The classical quadrature model is employed and the transconductor inherent nonlinear characteristic with input voltage is used as the amplitude-stabilization element. An external bias VTUNE linearly adjusts the oscillation frequency. According to a standard 0.8μm CMOS n-well process, a prototype was integrated, with an effective area of 0.28mm2. Experimental data validate the theoretical analysis. For a single 1.8V-supply and 100mV≤VTUNE≤250mV, the oscillation frequency fo ranges from 0.50MHz to 1.125MHz, with a nearly constant gain KVCO=4.16KHz/mV. Maximum output amplitude is 374mVpp @1.12MHz. THD is -41dB @321mVpp. Maximum average consumption is 355μW.

Specific and nonspecific collapse in protein folding funnels

Experiments with fast folding proteins are beginning to address the relationship between collapse and folding. We investigate how different scenarios for folding can arise depending on whether the folding and collapse transitions are concurrent or whether a nonspecific collapse precedes folding. Many earlier studies have focused on the limit in which collapse is fast compared to the folding time; in this work we focus on the opposite limit where, at the folding temperature, collapse and folding occur simultaneously. Real proteins exist in both of these limits. The folding mechanism varies substantially in these two regimes. In the regime of concurrent folding and collapse, nonspecific collapse now occurs at a temperature below the folding temperature (but slightly above the glass transition temperature).

Steric constraints as folding coadjuvant

Through the analyses of the Miyazawa-Jernigan matrix it has been shown that the hydrophobic effect generates the dominant driving force for protein folding. By using both lattice and off-lattice models, it is shown that hydrophobic-type potentials are indeed efficient in inducing the chain through nativelike configurations, but they fail to provide sufficient stability so as to keep the chain in the native state. However, through comparative Monte Carlo simulations, it is shown that hydrophobic potentials and steric constraints are two basic ingredients for the folding process. Specifically, it is shown that suitable pairwise steric constraints introduce strong changes on the configurational activity, whose main consequence is a huge increase in the overall stability condition of the native state; detailed analysis of the effects of steric constraints on the heat capacity and configurational activity are provided. The present results support the view that the folding problem of globular proteins can be approached as a process in which the mechanism to reach the native conformation and the requirements for the globule stability are uncoupled.

A low-voltage low-sensitivity sinusoidal VCO for DPLL realizations

A quasi-sinusoidal linearly tunable OTA-C VCO built with triode-region transconductors is presented. Oscillation upon power-on is ensured by RHP poles associated with gate-drain capacitances of OTA input devices. Since the OTA nonlinearity stabilizes the amplitude, the oscillation frequency f0 is first-order independent of VDD, making the VCO adequate to mixed-mode designs. A range of simulations attests the theoretical analysis. As part of a DPLL, the VCO was prototyped on a 0.8μm CMOS process, occupying an area of 0.15mm2. Nominal f0 is 1MHz, with K VCo=8.4KHz/mV. Measured sensitivity to VDD is below 2.17, while phase noise is -86dBc at 100-KHz offset. The feasibility of the VCO for higher frequencies is verified by a redesign based on a 0.35μm CMOS process and VDD=3.3V, with a linear frequency-span of l3.2MHz - 61.5MHz.

Comparative analysis for reactive energy measurement methodologies, under non-sinusoidal conditions in three-phase four-wire circuits

This paper presents some methodologies for reactive energy measurement, considering three modern power theories that are suitable for three-phase four-wire non-sinusoidal and unbalanced circuits. The theories were applied in some profiles collected in electrical distribution systems which have real characteristics for voltages and currents measured by commercial reactive energy meters. The experimental results are presented in order to analyze the accuracy of the methodologies, considering the standard IEEE 1459-2010 as a reference. Finally, for additional comparisons, the theories will be confronted with the modern Yokogawa WT3000 energy meter and three samples of a commercial energy meter through an experimental setup. © 2011 IEEE.

An analysis of Generalized Symmetrical Components in non sinusoidal three phase systems

This paper presents the study of the so called Generalized Symmetrical Components, proposed by Tenti et. al. to the analysis of unbalanced periodic non sinusoidal three phase systems. As a result, it was possible to establish a proper relationship between such of generalized symmetrical components and Fortescue symmetrical components to the harmonic frequencies that compose a generic periodic non sinusoidal three phase system. © 2011 IEEE.

Practical comparisons among electronic energy meters, a precision energy meter and IEEE1459 for reactive energy measurements, under unbalanced and non-sinusoidal conditions

This paper presents a practical experimentation for comparing reactive/non-active energy measures, considering three-phase four-wire non-sinusoidal and unbalanced circuits, involving five different commercial electronic meters. The experimentation set provides separately voltage and current generation, each one with any waveform involving up to fifty-first harmonic components, identically compared with acquisitions obtained from utility. The experimental accuracy is guaranteed by a class A power analyzer, according to IEC61000-4-30 standard. Some current and voltage combination profiles are presented and confronted with two different references of reactive/non-active calculation methodologies; instantaneous power theory and IEEE 1459-2010. The first methodology considers the instantaneous power theory, present into the advanced mathematical internal algorithm from WT3000 power analyzer, and the second methodology, accomplish with IEEE 1459-2010 standard, uses waveform voltage and current acquisition from WT3000 as input data for a virtual meter developed on Mathlab/Simulink software. © 2012 IEEE.

Analyzing the effect of homogeneous frustration in protein folding

The energy landscape theory has been an invaluable theoretical framework in the understanding of biological processes such as protein folding, oligomerization, and functional transitions. According to the theory, the energy landscape of protein folding is funneled toward the native state, a conformational state that is consistent with the principle of minimal frustration. It has been accepted that real proteins are selected through natural evolution, satisfying the minimum frustration criterion. However, there is evidence that a low degree of frustration accelerates folding. We examined the interplay between topological and energetic protein frustration. We employed a Cα structure-based model for simulations with a controlled nonspecific energetic frustration added to the potential energy function. Thermodynamics and kinetics of a group of 19 proteins are completely characterized as a function of increasing level of energetic frustration. We observed two well-separated groups of proteins: one group where a little frustration enhances folding rates to an optimal value and another where any energetic frustration slows down folding. Protein energetic frustration regimes and their mechanisms are explained by the role of non-native contact interactions in different folding scenarios. These findings strongly correlate with the protein free-energy folding barrier and the absolute contact order parameters. These computational results are corroborated by principal component analysis and partial least square techniques. One simple theoretical model is proposed as a useful tool for experimentalists to predict the limits of improvements in real proteins. © 2013 Wiley Periodicals, Inc.