On the role of entropy in the stabilization of α-helices

Protein folding evolves by exploring the conformational space with a subtle balance between enthalpy and entropy changes which eventually leads to a decrease of free energy upon reaching the folded structure. A complete understanding of this process requires, therefore, a deep insight into both contributions to free energy. In this work, we clarify the role of entropy in favoring the stabilization of folded structures in polyalanine peptides with up to 12 residues. We use a novel method referred to as K2V that allows us to obtain the potential-energy landscapes in terms of residue conformations extracted from molecular dynamics simulations at conformational equilibrium and yields folding thermodynamic magnitudes, which are in agreement with the experimental data available. Our results demonstrate that the folded structures of the larger polyalanine chains are stabilized with respect to the folded structures of the shorter chains by both an energetic contribution coming from the formation of the intramolecular hydrogen bonds and an entropic contribution coming from an increase of the entropy of the solvent with approximate weights of 60 and 40%, respectively, thus unveiling a key piece in the puzzle of protein folding. In addition, the ability of the K2V method to provide the enthalpic and entropic contributions for individual residues along the peptide chain makes it clear that the energetic and entropic stabilizations are basically governed by the nearest neighbor residue conformations, with the folding propensity being rationalized in terms of triads of residuesThis work was partially supported by the Spanish AgenciaEstatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, UE) under Project CTQ2016-79345-P and by the Fundación Séneca under Project 20789/PI/18. We thank the computational assistance provided by J.F.Hidalgo of the Servicio de Infraestructuras TIC de ATIC

On the role of entropy in the stabilization of α-Helixes

Protein folding evolves by exploring the conformational space with a subtle balance between enthalpy and entropy changes which eventually leads to a decrease of free energy upon reaching the folded structure. A complete understanding of this process requires, therefore, a deep insight into both contributions to free energy. In this work, we clarify the role of entropy in favoring the stabilization of folded structures in polyalanine peptides with up to 12 residues. We use a novel method referred to as K2V that allows us to obtain the potential-energy landscapes in terms of residue conformations extracted from molecular dynamics simulations at conformational equilibrium and yields folding thermodynamic magnitudes, which are in agreement with the experimental data available. Our results demonstrate that the folded structures of the larger polyalanine chains are stabilized with respect to the folded structures of the shorter chains by both an energetic contribution coming from the formation of the intramolecular hydrogen bonds and an entropic contribution coming from an increase of the entropy of the solvent with approximate weights of 60 and 40%, respectively, thus unveiling a key piece in the puzzle of protein folding. In addition, the ability of the K2V method to provide the enthalpic and entropic contributions for individual residues along the peptide chain makes it clear that the energetic and entropic stabilizations are basically governed by the nearest neighbor residue conformations, with the folding propensity being rationalized in terms of triads of residuesThis work was partially supported by the Spanish Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, UE) under Project CTQ2016-79345-P and by the Fundación Séeneca under Project 20789/PI/18. We thank the computational assistance provided by J. F. Hidalgo of the Servicio de Infraestructuras TIC de ATICA

The resonance raman spectrum of cytosine in water: analysis of the effect of specific solute–solvent interactions and non-adiabatic couplings

In this contribution, we report a computational study of the vibrational Resonance Raman (vRR) spectra of cytosine in water, on the grounds of potential energy surfaces (PES) computed by time-dependent density functional theory (TD-DFT) and CAM-B3LYP and PBE0 functionals. Cytosine is interesting because it is characterized by several close-lying and coupled electronic states, challenging the approach commonly used to compute the vRR for systems where the excitation frequency is in quasi-resonance with a single state. We adopt two recently developed time-dependent approaches, based either on quantum dynamical numerical propagations of vibronic wavepackets on coupled PES or on analytical correlation functions for cases in which inter-state couplings were neglected. In this way, we compute the vRR spectra, considering the quasi-resonance with the eight lowest-energy excited states, disentangling the role of their inter-state couplings from the mere interference of their different contributions to the transition polarizability. We show that these effects are only moderate in the excitation energy range explored by experiments, where the spectral patterns can be rationalized from the simple analysis of displacements of the equilibrium positions along the different states. Conversely, at higher energies, interference and inter-state couplings play a major role, and the adoption of a fully non-adiabatic approach is strongly recommended. We also investigate the effect of specific solute–solvent interactions on the vRR spectra, by considering a cluster of cytosine, hydrogen-bonded by six water molecules, and embedded in a polarizable continuum. We show that their inclusion remarkably improves the agreement with the experiments, mainly altering the composition of the normal modes, in terms of internal valence coordinates. We also document cases, mostly for low-frequency modes, in which a cluster model is not sufficient, and more elaborate mixed quantum classical approaches, in explicit solvent models, need to be applie

Adiabatic-Molecular Dynamics Generalized Vertical Hessian Approach: A Mixed Quantum Classical Method to Compute Electronic Spectra of Flexible Molecules in the Condensed Phase

We present a general mixed quantum classical method that couples classical molecular dynamics (MD) and vibronic models to compute the shape of electronic spectra of flexible molecules in the condensed phase without, in principle, any phenomenological broadening. It is based on a partition of the nuclear motions of the solute + solvent system in "soft" and "stiff" vibrational modes and an adiabatic hypothesis that assumes that stiff modes are much faster than soft ones. In this framework, the spectrum is rigorously expressed as a conformational integral of quantum vibronic spectra along the stiff coordinates only. Soft modes enter at the classical level through the conformational distribution that is sampled with classical MD runs. In each configuration, reduced-dimensionality quadratic Hamiltonians are built in the space of the stiff coordinates only, thanks to a generalization of the Vertical Hessian harmonic model and an iterative application of projectors in internal coordinates to remove soft modes. Quantum vibronic spectra, specific for each sampled configuration of the soft coordinates, are then computed at the desired temperature with efficient time-dependent techniques, and the global spectrum simply arises from their average. For consistency of the whole procedure, classical MD runs are performed with quantum-mechanically derived force fields, parameterized at the same level of theory selected for generating the quadratic Hamiltonians along the stiff coordinates. Application to N-methyl-6-oxyquinolinium betaine in water, dithiophene in ethanol, and cyanidine in water is presented to show the performance of the methodThis work has received funding from the European Union’s Horizon 2020 research and innovation programme MSCA-ITN under grant agreement no. 765266 (LightDyNAmics). Computational resources provided by the Centro de Cálculo Científico at Universidad Autónoma de Madrid (CCC-UAM) and by SCBI (Supercomputing and Bioinformatics) center of Universidad de Málaga are also acknowledged. D.A. and F.A. acknowledge financial support from Spanish “Ministerio de Economía y Competitividad” (project CTQ2015-65816-R). D.A. acknowledges Fundación Ramón Areces (Spain) for funding his postdoctoral stay at ICCOM-CNR Pisa. J.C. and D.A. acknowledge the Pisa Unit of ICCOM-CNR for hospitality

Mixed Quantum/Classical Method for Nonadiabatic Quantum Dynamics in Explicit Solvent Models: The ππ∗/nπ∗ Decay of Thymine in Water as a Test Case

We present a novel mixed quantum classical dynamical method to include solvent effects on internal conversion (IC) processes. All the solute degrees of freedom are represented by a wavepacket moving according to nonadiabatic quantum dynamics, while the motion of an explicit solvent model is described by an ensemble of classical trajectories. The mutual coupling of the solute and solvent dynamics is included within a mean-field framework and the quantum and classical equations of motions are solved simultaneously. As a test case we apply our method to the ultrafast ππ∗ → nπ∗ decay of thymine in water. Solvent dynamical response modifies IC yield already on the 50 fs time scale. This effect is due to water librational motions that stabilize the most populated state. Pure static disorder, that is, the existence of different solvent configurations when photoexcitation takes place, also has a remarkable impact on the dynamicsThe support of MIUR (PRIN 2010-2011 prot. 2010ERFKXL) is acknowledged. J.C. acknowledges the Fundacioń Ramoń Areces for funding his Postdoctoral position in Pisa and the fellowship provided by “Fundacioń Seńeca − Agencia de Ciencia y Tecnología de la Regioń de Murcia” through the “Saavedra-Fajardo” program (20028/SF/16). R.I. thanks the Université Paris-Saclay (Chaire d’Alembert No. 2016-10751). Y. L. acknowledges the financial support from the China Scholarship Council (CSC, No. 201506220064) and Y.L. and N. L. a generous grant of computer time from the Norwegian Programme for Supercomputing. N. L. also acknowledges the National Nature Science Foundation of China (Grant No. 21573129). The authors gratefully acknowledge G. Worth for making available the Quantics code and for useful discussion

Turn on fluorescence sensing of Zn2+ based on fused isoindole-imidazole scaffold

Optical chemosensors caused a revolution in the field of sensing due to their high specificity, sensitivity, and fast detection features. Imidazole derivatives have offered promising features in the literature as they bear suitable donor/acceptor groups for the selective analytes in the skeleton. In this work, an isoindole-imidazole containing a Schiff base chemosensor (1-{3-[(2-Diethylamino-ethylimino)-methyl]-2-hydroxy-5-methyl-phenyl}-2H-imidazo[5,1-a]isoindole-3,5-dione) was de-signed and synthesized. The complete sensing phenomena have been investigated by means of UV-Vis, fluorescence, lifetime measurement, FT-IR, NMR and ESI-MS spectroscopic techniques. The optical properties of the synthesized ligand were investigated in 3:7 HEPES buffer:DMSO medium and found to be highly selective and sensitive toward Zn2+ ion through a fluorescence turn-on response with detection limit of 0.073 µm. Furthermore, this response is effective in gel form also. The competition studies reveal that the response of the probe for Zn2+ ion is unaffected by other relevant metal ions. The stoichiometric binding study was performed utilizing Job’s method which indicated a 1:1 sensor–Zn2+ ensemble. Computational calculations were performed to pinpoint the mechanism of sensin

Caracterización teórica de la acción de ácidos grasos y carotenoides en membranas y fotosistemas.

En esta Tesis abordamos la caracterización de ácidos grasos y carotenoides en sistemas de gran relevancia biológica, como lo son las membranas celulares y los fotosistemas. Empleamos para ello técnicas computacionales tanto de la mecánica cuántica como de la mecánica molecular, que ofrecen una descripción detallada, a escala atómica, de los fenómenos químicos que tienen lugar en estos entornos. Así, en este trabajo se construyen modelos para caracterizar la actividad antioxidante de los carotenoides basados en cálculos de la teoría del funcional de la densidad (DFT), al tiempo que se desarrollan campos de fuerza empíricos para describir la conformación y las interacciones moleculares de ácidos grasos y carotenoides en los medios biológicos, que permiten su simulación mediante la dinámica molecular. Las perturbaciones estructurales producidas por los ácidos grasos con insaturaciones cis sobre las membranas juegan un papel clave en la acción terapéutica que muestran estas moléculas, y nuestros resultados muestran, específicamente, el efecto del ácido oleico y el ácido 2-hidroxioleico, destacando las diferencias entre ambos que conducen a su diferenciada actividad terapéutica. En el caso de los carotenoides, resultan más relevantes, sin embargo, las perturbaciones que produce el entorno de la membrana celular o el fotosistema sobre su cadena conjugada. La conformación de esta cadena es la que marca la actividad antioxidante y espectroscópica de estas moléculas, lo que se relaciona con su acción terapéutica. Las propiedades espectroscópicas de los carotenoides resultan de gran importancia para explicar su acción biológica en fotosistemas y, por ello, se han estudiado más detenidamente para dos carotenoides: beta-caroteno y violaxantina. Hemos caracterizado, mediante cálculos DFT y DFT dependientes del tiempo (TD-DFT) y usando modelos armónicos, las superficies de energía potencial de los estados electrónicos de baja energía entre los que se produce el transito de dipolo permitido en estas moléculas, simulando además el correspondiente espectro electrónico con resolución vibracional por medio de técnicas de la espectroscopía computacional, en formulaciones independientes y dependientes del tiempo. Nuestros resultados proporcionan espectros electrónicos de estos carotenoides a temperatura criogénica y temperatura ambiente, que pueden compararse directamente con los experimentales. ABSTRACT: In this Thesis, we perform the characterization of both fatty acids and carotenoids within relevant biological systems as cell membranes and photosystems. To that end, we apply computational techniques, both at quantum mechanics and molecular mechanics levels, which provide a detailed atomistic description of the chemical phenomena that take place within such environments. Concretely, in this work, models are constructed to characterize the antioxidant activity of carotenoids based on Density Functional Theory (DFT) calculations, and empiric force fields are also developed in order to describe the conformation and intermolecular interactions of fatty acids and carotenoids within the complex biological environments, thus allowing their simulations by means of molecular dynamics techniques. The structural perturbations produced by the fatty acids cis double bonds play a key role in the therapeutic mechanisms of these molecules, and our results show, specifically, the effect of oleic acid and 2-hydroxyoleic acid, highlighting the differences between them that eventually lead to their distinct therapeutic activity. In the case of carotenoids, however, the perturbations that the complex environment of the lipid bilayer or the photosystem induce on their conjugated chain reveals more important. The conformation of such hydrocarbon chain actually dictates the antioxidant and spectroscopic properties of these molecules, which, in turn, are related with their therapeutic activity. The spectroscopic properties of carotenoids are extremely important for their biological activity within photosystems and, therefore, they have been evaluated more in detail for two carotenoids: beta-carotene and violaxanthin. We have characterized, through DFT and Time Dependent DFT (TD-DFT) computations and using harmonic models, the potential energy surfaces of the low lying electronic states between which the allowed dipole transition in these molecules occur, also simulating the corresponding vibrationally resolved electronic spectrum by means of computational spectroscopic techniques, both adopting time independent and time dependent approaches. Our results provide the spectra at both cryogenic and room temperature, directly comparable with the experimental ones

Energetic Self-Folding Mechanism in α-Helixes

A novel energetic route driving the folding of a polyalanine peptide from an extended conformation to its α-helix native conformation is described, supported by a new method to compute mean potential energy surfaces accurately in terms of the dihedral angles of the peptide chain from extensive Molecular Dynamics simulations. The Energetic Self-Folding (ESF) route arises specifically from the balance between the intrinsic propensity of alanine residues towards the αR conformation and two, opposite, effects: the destabilizing interaction with neighbor residues and the stabilizing formation of native hydrogen bonds, with the latter being dominant for large peptide lengths. The ESF mechanism provides simple but robust support to the nucleation-elongation, or zipper models, and offers a quantitative energetic funnel picture of the folding process. The mechanism is validated by the reasonable agreement between the computed folding energies and the experimental values

Intraresidual Correlated Motions in Peptide Chain

Conformational flexibility of polypeptide chains is mainly driven by changes in the (phi, psi) dihedrals of each residue. Such motions, however, are not completely independent, as certain (anti)correlated motions are favored. In this work, we investigate the correlations between the dihedral displacements of adjacent residues, (Δphi i, Δpsi i+1) and (Δphi i-1, Δpsi i), i.e. interresidual, and within the same residue, (Δphi i, Δpsi i), i.e. intraresidual, by analyzing extensive Molecular Dynamics trajectories of initially extended polyalanine chains in detail. Correlations are evaluated individually at different residue conformations covering the whole (phi, psi)-space. From these we draw maps which clearly show how the coupled motions strongly depend on the conformation, thus unveiling an unprecedented strong intramolecular correlation displaying opposite (correlated/anticorrelated) behaviors at different conformations. By developing a tailored model, it is also demonstrated that both inter and intraresidual correlations arise from the propensity of the peptide to minimize the overall atomic displacements along the whole polypeptide chain