Priming for Performance: Valence of Emotional Primes Interact with Dissociable Prototype Learning Systems

Arousal Biased Competition theory suggests that arousal enhances competitive attentional processes, but makes no strong claims about valence effects. Research suggests that the scope of enhanced attention depends on valence with negative arousal narrowing and positive arousal broadening attention. Attentional scope likely affects declarative-memory-mediated and perceptual-representation-mediated learning systems differently, with declarative-memory-mediated learning depending on narrow attention to develop targeted verbalizable rules, and perceptual-representation-mediated learning depending on broad attention to develop a perceptual representation. We hypothesize that negative arousal accentuates declarative-memory-mediated learning and attenuates perceptual-representation-mediated learning, while positive arousal reverses this pattern. Prototype learning provides an ideal test bed as dissociable declarative-memory and perceptual-representation systems mediate two-prototype (AB) and one-prototype (AN) prototype learning, respectively, and computational models are available that provide powerful insights on cognitive processing. As predicted, we found that negative arousal narrows attentional focus facilitating AB learning and impairing AN learning, while positive arousal broadens attentional focus facilitating AN learning and impairing AB learning.     

Free-Energy Landscape and Characteristic Forces for the Initiation of DNA Unzipping

DNA unzipping, the separation of its double helix into single strands, is crucial in modulating a host of genetic processes. Although the large-scale separation of double-stranded DNA has been studied with a variety of theoretical and experimental techniques, the minute details of the very first steps of unzipping are still unclear. Here, we use atomistic molecular-dynamics simulations, coarse-grained simulations, and a statistical-mechanical model to study the initiation of DNA unzipping by an external force. Calculation of the potential of mean force profiles for the initial separation of the first few terminal basepairs in a DNA oligomer revealed that forces ranging between 130 and 230 pN are needed to disrupt the first basepair, and these values are an order of magnitude larger than those needed to disrupt basepairs in partially unzipped DNA. The force peak has an echo of ∼50 pN at the distance that unzips the second basepair. We show that the high peak needed to initiate unzipping derives from a free-energy basin that is distinct from the basins of subsequent basepairs because of entropic contributions, and we highlight the microscopic origin of the peak. To our knowledge, our results suggest a new window of exploration for single-molecule experiments.     

A Free-Energy Approach for All-Atom Protein Simulation

All-atom free-energy methods offer a promising alternative to kinetic molecular mechanics simulations of protein folding and association. Here we report an accurate, transferable all-atom biophysical force field (PFF02) that stabilizes the native conformation of a wide range of proteins as the global optimum of the free-energy landscape. For 32 proteins of the ROSETTA decoy set and six proteins that we have previously folded with PFF01, we find near-native conformations with an average backbone RMSD of 2.14 Å to the native conformation and an average Z-score of −3.46 to the corresponding decoy set. We used nonequilibrium sampling techniques starting from completely extended conformations to exhaustively sample the energy surface of three nonhomologous hairpin-peptides, a three-stranded β-sheet, the all-helical 40 amino-acid HIV accessory protein, and a zinc-finger ββα motif, and find near-native conformations for the minimal energy for each protein. Using a massively parallel evolutionary algorithm, we also obtain a near-native low-energy conformation for the 54 amino-acid engrailed homeodomain. Our force field thus stabilized near-native conformations for a total of 20 proteins of all structure classes with an average RMSD of only 3.06 Å to their respective experimental conformations.     

Thermodynamics of Light Emission and Free-Energy Storage in Photosynthesis

A Planck law relationship between absorption and emission spectra is used to compute the fluorescence spectra of some photosynthetic systems from their absorption spectra. Calculated luminescence spectra of purple bacteria agree well but not perfectly with published experimental spectra. Application of the Planck law relation to published activation spectra for Systems I and II of spinach chloroplasts permits independent calculation of the luminescence spectra of the two systems; if the luminescence yield of System I is taken to be one-third the yield of System II, then the combined luminescence spectrum closely fits published experimental measurement.

Consideration of the entropy associated with the excited state of the absorbing molecules is used to compute the oxidation-reduction potentials and maximum free-energy storage resulting from light absorption. Spinach chloroplasts under an illumination of 1 klux of white light can produce at most a potential difference of 1.32 ev for System I, and 1.36 ev for System II. In the absence of nonradiative losses, the maximum amount of free energy stored is 1.19 ev and 1.23 ev per photon absorbed for Systems I and II, respectively. The bacterium Chromatium under an illumination of 1 mw/cm² of Na D radiation can produce at most a potential difference of 0.90 ev; the maximum amount of free energy stored is 0.79 ev per photon absorbed.

The combined effect of partial thermodynamic reversibility and a finite trapping rate on the amount of luminescence is considered briefly.

     

Role of Small Oligomers on the Amyloidogenic Aggregation Free-Energy Landscape

We combine atomic-force-microscopy particle-size-distribution measurements with earlier measurements on 1-anilino-8-naphthalene sulfonate, thioflavin T, and dynamic light scattering to develop a quantitative kinetic model for the aggregation of β-lactoglobulin into amyloid. We directly compare our simulations to the population distributions provided by dynamic light scattering and atomic force microscopy. We combine species in the simulation according to structural type for comparison with fluorescence fingerprint results. The kinetic model of amyloidogenesis leads to an aggregation free-energy landscape. We define the roles of and propose a classification scheme for different oligomeric species based on their location in the aggregation free-energy landscape. We relate the different types of oligomers to the amyloid cascade hypothesis and the toxic oligomer hypothesis for amyloid-related diseases. We discuss existing kinetic mechanisms in terms of the different types of oligomers. We provide a possible resolution to the toxic oligomer-amyloid coincidence.     

Linear Free-Energy Relationships and the Dynamics of Gating in the Acetylcholine Receptor Channel

The muscle acetylcholine receptor channel (AChR) is a large (M_r 290K) transmembrane protein that mediates synaptic transmission. Theactivation of this ion channel can be understood in the framework of athermodynamic cycle with spontaneous gating (i.e., the closed open reaction) and ligand-binding events as the elementary steps. Becauseagonists bind more tightly to the open than to the closed state, gating ofliganded receptors is more favorable than that of unliganded receptors.Accordingly, channel opening must involve two major conformationalchanges: the ACh-binding sites switch from a low-affinity to a high-affinityform, and the pore (located 45 Å away from the binding sites)switches from an ion-impermeable to an ion-permeable conformation. Togain insight into the reaction mechanism of fully-liganded gating, wecharacterized the corresponding transition state in the context of the `linearfree-energy relationships' of physical organic chemistry (-valueanalysis). Gating of fully-liganded AChRs was studied by recordingsingle-channel currents using the patch-clamp technique. Perturbations tothe wild-type receptor were either series of different mutations at individualpositions or series of different agonists. Based on the obtained `snapshot'of the gating reaction at the transition state, and aware of the lack ofinformation about the rest of the energy profile, the most parsimoniousmechanism seems to be one where opening proceeds asynchronously, withthe low-to-high affinity change at the binding sites preceding the completeopening of the distant pore.     

Autonomic Effects of Music in Health and Crohn's Disease: The Impact of Isochronicity,Emotional Valence,and Tempo

BackgroundMusic can evoke strong emotions and thus elicit significant autonomic nervous system (ANS) responses. However, previous studies investigating music-evoked ANS effects produced inconsistent results. In particular, it is not clear (a) whether simply a musical tactus (without common emotional components of music) is sufficient to elicit ANS effects; (b) whether changes in the tempo of a musical piece contribute to the ANS effects; (c) whether emotional valence of music influences ANS effects; and (d) whether music-elicited ANS effects are comparable in healthy subjects and patients with Crohn´s disease (CD, an inflammatory bowel disease suspected to be associated with autonomic dysfunction).MethodsTo address these issues, three experiments were conducted, with a total of n = 138 healthy subjects and n = 19 CD patients. Heart rate (HR), heart rate variability (HRV), and electrodermal activity (EDA) were recorded while participants listened to joyful pleasant music, isochronous tones, and unpleasant control stimuli.ResultsCompared to silence, both pleasant music and unpleasant control stimuli elicited an increase in HR and a decrease in a variety of HRV parameters. Surprisingly, similar ANS effects were elicited by isochronous tones (i.e., simply by a tactus). ANS effects did not differ between pleasant and unpleasant stimuli, and different tempi of the music did not entrain ANS activity. Finally, music-evoked ANS effects did not differ between healthy individuals and CD patients.ConclusionsThe isochronous pulse of music (i.e., the tactus) is a major factor of music-evoked ANS effects. These ANS effects are characterized by increased sympathetic activity. The emotional valence of a musical piece contributes surprisingly little to the ANS activity changes evoked by that piece.     

Free-Energy Perturbation Simulation on Transition States and Redesign of Butyrylcholinesterase

It is recognized that an ideal anti-cocaine treatment is to accelerate cocaine metabolism by producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e., butyrylcholinesterase (BChE)-catalyzed hydrolysis of cocaine. BChE mutants with a higher catalytic activity against (-)-cocaine are highly desired for use as an exogenous enzyme in humans. To develop a rational design for high-activity mutants, we carried out free-energy perturbation (FEP) simulations on various mutations of the transition-state structures in addition to the corresponding free-enzyme structures by using an extended FEP procedure. The FEP simulations on the mutations of both the free-enzyme and transition-state structures allowed us to calculate the mutation-caused shift of the free-energy change from the free enzyme (BChE) to the transition state, and thus to theoretically predict the mutation-caused shift of the catalytic efficiency (k_cat/K_M). The computational predictions are supported by the kinetic data obtained from the wet experiments, demonstrating that the FEP-based computational design approach is promising for rational design of high-activity mutants of an enzyme. One of the BChE mutants designed and discovered in this study has an ∼1800-fold improved catalytic efficiency against (-)-cocaine compared to wild-type BChE. The high-activity mutant may be therapeutically valuable.     

Conformational Free-Energy Landscapes for a Peptide in Saline Environments

The conformations that proteins adopt in solution are a function of both their primary structure and surrounding aqueous environment. Recent experimental and computational work on small peptides, e.g., polyK, polyE, and polyR, have highlighted an interesting and unusual behavior in the presence of aqueous ions such as ClO₄⁻, Na⁺, and K⁺. Notwithstanding the aforementioned studies, as of this writing, the nature of the driving force induced by the presence of ions and its role on the conformational stability of peptides remains only partially understood. Molecular-dynamics simulations have been performed on the heptapeptide AEAAAEA in NaCl and KCl solutions at concentrations of 0.5, 1.0, and 2.0 M. Metadynamics in conjunction with a three-dimensional model reaction coordinate was used to sample the conformational space of the peptide. All simulations were run for 2 μs. Free-energy landscapes were computed over the model reaction coordinate for the peptide in each saline assay as well as in the absence of ions. Circular dichroism spectra were also calculated from each trajectory. In the presence of Na⁺ and K⁺ ions, no increase in helicity is observed with respect to the conformation in pure water.     

Particle Diffusivity and Free-Energy Profiles in Hydrogels from Time-Resolved Penetration Data

A combined experimental and theoretical method to simultaneously determine diffusivity and free-energy profiles of particles that penetrate into inhomogeneous hydrogel systems is presented. As the only input, arbitrarily normalized concentration profiles from fluorescence intensity data of labeled tracer particles for different penetration times are needed. The method is applied to dextran molecules of varying size that penetrate into hydrogels of polyethylene-glycol chains with different lengths that are covalently cross-linked by hyperbranched polyglycerol hubs. Extracted dextran bulk diffusivities agree well with fluorescence correlation spectroscopy data obtained separately. Empirical scaling laws for dextran diffusivities and free energies inside the hydrogel are identified as a function of the dextran mass. An elastic free-volume model that includes dextran as well as polyethylene-glycol linker flexibility quantitively describes the repulsive dextran-hydrogel interaction free energy, which is of steric origin, and furthermore suggests that the hydrogel mesh-size distribution is rather broad and particle penetration is dominated by large hydrogel pores. Particle penetration into hydrogels for steric particle-hydrogel interactions is thus suggested to be governed by an elastic size-filtering mechanism that involves the tail of the hydrogel pore-size distribution.     

Free-Energy Landscapes for Macromolecules that Form a Unique 3D Structure

Biophysics - Abstract—The entropic effects for the energy landscapes of macromolecules are considered. We use the ideas and methods of multidimensional geometry and topology, expansion into a...     

Elbow Flexibility of the kt38 RNA Kink-Turn Motif Investigated by Free-Energy Molecular Dynamics Simulations

Kink-turns (K-turns) are common structural motifs that can introduce sharp kinks into double-stranded RNA, and have been proposed to mediate large-scale motions in the ribosome. K-turns consist of a bulge loop region flanked by trans sugar-Hoogsteen G:A pairs, and the sharp kink conformation is stabilized by A-minor interactions (adenine contacting a G:C basepair in the minor groove). Umbrella-sampling molecular dynamics simulations were used to disrupt an A-minor interaction in the ribosomal kt38 turn and to calculate the associated free-energy change. Coupling of umbrella sampling with replica exchanges between neighboring umbrella-sampling intervals could further improve the convergence of the free-energy calculations. The simulations revealed a coupled A-minor disruption and global opening of the K-turn motif, and allowed us to characterize several intermediate A-minor conformations. The calculated free-energy profile indicated a meta-stable, semi-open structure of slightly higher free energy (∼1 kcal mol⁻¹), separated by a small free-energy barrier (∼1.5 kcal mol⁻¹) from the closed (highly kinked) form. Both K-turn states are stabilized by distinct variants of the A-minor interaction. Further opening of the K-turn structure required significantly larger free-energy changes. The semi-open form had a reduced kink angle compatible with experimental data on K-turn solution structures, and opening was coupled to a continuous global unwinding of the K-turn motif. The range of free-energy changes associated with kt38 opening and unwinding are compatible with the idea that K-turns may facilitate biologically relevant motions during large-scale ribosome dynamics.     

A Potent and Selective Peptide Blocker of the Kv1.3 Channel: Prediction from Free-Energy Simulations and Experimental Confirmation

The voltage-gated potassium channel Kv1.3 is a well-established target for treatment of autoimmune diseases. ShK peptide from a sea anemone is one of the most potent blockers of Kv1.3 but its application as a therapeutic agent for autoimmune diseases is limited by its lack of selectivity against other Kv channels, in particular Kv1.1. Accurate models of Kv1.x-ShK complexes suggest that specific charge mutations on ShK could considerably enhance its specificity for Kv1.3. Here we evaluate the K18A mutation on ShK, and calculate the change in binding free energy associated with this mutation using the path-independent free energy perturbation and thermodynamic integration methods, with a novel implementation that avoids convergence problems. To check the accuracy of the results, the binding free energy differences were also determined from path-dependent potential of mean force calculations. The two methods yield consistent results for the K18A mutation in ShK and predict a 2 kcal/mol gain in Kv1.3/Kv1.1 selectivity free energy relative to wild-type peptide. Functional assays confirm the predicted selectivity gain for ShK[K18A] and suggest that it will be a valuable lead in the development of therapeutics for autoimmune diseases.     

High Free-Energy Barrier of 1D Diffusion Along DNA by Architectural DNA-Binding Proteins

Architectural DNA-binding proteins function to regulate diverse DNA reactions and have the defining property of significantly changing DNA conformation. Although the 1D movement along DNA by other types of DNA-binding proteins has been visualized, the mobility of architectural DNA-binding proteins on DNA remains unknown. Here, we applied single-molecule fluorescence imaging on arrays of extended DNA molecules to probe the binding dynamics of three structurally distinct architectural DNA-binding proteins: Nhp6A, HU, and Fis. Each of these proteins was observed to move along DNA, and the salt concentration independence of the 1D diffusion implies sliding with continuous contact to DNA. Nhp6A and HU exhibit a single sliding mode, whereas Fis exhibits two sliding modes. Based on comparison of the diffusion coefficients and sizes of many DNA binding proteins, the architectural proteins are categorized into a new group distinguished by an unusually high free-energy barrier for 1D diffusion. The higher free-energy barrier for 1D diffusion by architectural proteins can be attributed to the large DNA conformational changes that accompany binding and impede rotation-coupled movement along the DNA grooves.     

On the Improvement of Free-Energy Calculation from Steered Molecular Dynamics Simulations Using Adaptive Stochastic Perturbation Protocols

The potential of mean force (PMF) calculation in single molecule manipulation experiments performed via the steered molecular dynamics (SMD) technique is a computationally very demanding task because the analyzed system has to be perturbed very slowly to be kept close to equilibrium. Faster perturbations, far from equilibrium, increase dissipation and move the average work away from the underlying free energy profile, and thus introduce a bias into the PMF estimate. The Jarzynski equality offers a way to overcome the bias problem by being able to produce an exact estimate of the free energy difference, regardless of the perturbation regime. However, with a limited number of samples and high dissipation the Jarzynski equality also introduces a bias. In our previous work, based on the Brownian motion formalism, we introduced three stochastic perturbation protocols aimed at improving the PMF calculation with the Jarzynski equality in single molecule manipulation experiments and analogous computer simulations. This paper describes the PMF reconstruction results based on full-atom molecular dynamics simulations, obtained with those three protocols. We also want to show that the protocols are applicable with the second-order cumulant expansion formula. Our protocols offer a very noticeable improvement over the simple constant velocity pulling. They are able to produce an acceptable estimate of PMF with a significantly reduced bias, even with very fast perturbation regimes. Therefore, the protocols can be adopted as practical and efficient tools for the analysis of mechanical properties of biological molecules.     

Action and Valence Modulate Choice and Choice-Induced Preference Change

Choices are not only communicated via explicit actions but also passively through inaction. In this study we investigated how active or passive choice impacts upon the choice process itself as well as a preference change induced by choice. Subjects were tasked to select a preference for unfamiliar photographs by action or inaction, before and after they gave valuation ratings for all photographs. We replicate a finding that valuation increases for chosen items and decreases for unchosen items compared to a control condition in which the choice was made post re-evaluation. Whether choice was expressed actively or passively affected the dynamics of revaluation differently for positive and negatively valenced items. Additionally, the choice itself was biased towards action such that subjects tended to choose a photograph obtained by action more often than a photographed obtained through inaction. These results highlight intrinsic biases consistent with a tight coupling of action and reward and add to an emerging understanding of how the mode of action itself, and not just an associated outcome, modulates the decision making process.     

Solvation Free Energy of the Peptide Group: Its Model Dependence and Implications for the Additive-Transfer Free-Energy Model of Protein Stability

The group-additive decomposition of the unfolding free energy of a protein in an osmolyte solution relative to that in water poses a fundamental paradox: whereas the decomposition describes the experimental results rather well, theory suggests that a group-additive decomposition of free energies is, in general, not valid. In a step toward resolving this paradox, here we study the peptide-group transfer free energy. We calculate the vacuum-to-solvent (solvation) free energies of (Gly)_n and cyclic diglycine (cGG) and analyze the data according to experimental protocol. The solvation free energies of (Gly)_n are linear in n, suggesting group additivity. However, the slope interpreted as the free energy of a peptide unit differs from that for cGG scaled by a factor of half, emphasizing the context dependence of solvation. However, the water-to-osmolyte transfer free energies of the peptide unit are relatively independent of the peptide model, as observed experimentally. To understand these observations, a way to assess the contribution to the solvation free energy of solvent-mediated correlation between distinct groups is developed. We show that linearity of solvation free energy with n is a consequence of uniformity of the correlation contributions, with apparent group-additive behavior in the water-to-osmolyte transfer arising due to their cancellation. Implications for inferring molecular mechanisms of solvent effects on protein stability on the basis of the group-additive transfer model are suggested.