1,721,075 research outputs found
Cooperative protein-solvent tuning of proton transfer energetics: Carbonic anhydrase as a case study
No full textWe investigate the coupling between the proton transfer (PT) energetics and the protein-solvent dynamics using the intra-molecular PT in wild type (wt) human carbonic anhydrase II and its ten-fold faster mutant Y7F/N67Q as a test case. We calculate the energy variation upon PT, and from that we also calculate the PT reaction free energy, making use of a hybrid quantum mechanics/molecular dynamics approach. In agreement with the experimental data, we obtain that the reaction free energy is basically the same in the two systems. Yet, we show that the instantaneous PT energy is on average lower in the mutant possibly contributing to the faster PT rate. Analysis of the contribution to the PT energetics of the solvent and of each protein residue, also not in the vicinity of the active site, provides evidence for electrostatic tuning of the PT energy arising from the combined effect of the solvent and the protein environment. These findings open up a way to the more general task of the rational design of mutants with either enhanced or reduced PT rate
Revisiting the “Cluster-In-Solvent” Approach for Computational Spectroscopy: The Vibrational Circular Dichroism as a Test Case
Full text linkThe cluster-in-solvent approach, that is, the use of the quantum-mechanical calculation of a spectral observable on a significant number of solute–solvent clusters extracted from semi-classical simulations, is widely used in computational spectroscopy. However, identifying relevant coordinates for cluster selection remains a challenge. We previously developed the Ellipsoid Method for Cluster-in-Solvent (EMCS), an automated strategy for unbiased identification and statistical weighting of clusters. Yet, for larger solutes, EMCS can yield overly large solvent clusters that hinder conformational analysis. Here, we introduce a simple extension of EMCS that reduces cluster size, enabling its application to medium-to-large solutes. The method is validated through the computation of Vibrational Circular Dichroism (VCD) spectra, which are highly sensitive to solute–solvent interactions. Test cases include aqueous L-alanine, aqueous dialanine, and (1S,2S)-trans-1-amino-2-indanol in DMSO. For L-alanine and trans-1-amino-2-indanol, computed spectra closely match experiment, with root-mean-square-deviation (RMSD) values of 10.3 and 8.0, respectively, consistent with previous benchmarks. For aqueous dialanine, the main spectral features were reproduced, though discrepancies in the fine structure remain, likely due to limitations in capturing subtle solvation effects. Overall, the refined EMCS protocol enables efficient and non-arbitrary sampling of solute–solvent clusters, offering a valuable tool for the structural analysis of solvation shells in complex molecular systems
High Water Density at Non-Ice-Binding Surfaces Contributes to the Hyperactivity of Antifreeze Proteins
Full text linkAntifreeze proteins (AFPs) can bind to ice nuclei thereby inhibiting their growth and their hydration shell is believed to play a fundamental role. Here, we use molecular dynamics simulations to characterize the hydration shell of four moderately-active and four hyperactive AFPs. The local water density around the ice-binding-surface (IBS) is found to be lower than that around the non-ice-binding surface (NIBS) and this difference correlates with the higher hydrophobicity of the former. While the water-density increase (with respect to bulk) around the IBS is similar between moderately-active and hyperactive AFPs, it differs around the NIBS, being higher for the hyperactive AFPs. We hypothesize that while the lower water density at the IBS can pave the way to protein binding to ice nuclei, irrespective of the antifreeze activity, the higher density at the NIBS of the hyperactive AFPs contribute to their enhanced ability in inhibiting ice growth around the bound AFPs
Thermodynamic and kinetic characterization of a beta-hairpin peptide in solution: An extended phase space sampling by molecular dynamics simulations in explicit water
No full textThe folding of the amyloidogenic H1 peptide MKHMAGAAAAGAVV taken from the syrian hamster prion protein is explored in explicit aqueous solution at 300 K using long time scale all-atom molecular dynamics simulations for a total simulation time of 1.1 mu s. The system, initially modeled as an alpha-helix, preferentially adopts a beta-hairpin structure and several unfolding/refolding events are observed, yielding a very short average beta-hairpin folding time of similar to 200 ns. The long time scale accessed by our simulations and the reversibility of the folding allow to properly explore the configurational space of the peptide in solution. The free energy profile, as a function of the principal components (essential eigenvectors) of motion, describing the main conformational transitions, shows the characteristic features of a funneled landscape, with a downhill surface toward the beta-hairpin folded basin. However, the analysis of the peptide thermodynamic stability, reveals that the beta-hairpin in solution is rather unstable. These results are in good agreement with several experimental evidences, according to which the isolated H1 peptide adopts very rapidly in water beta-sheet structure, leading to amyloid fibril precipitates [Nguyen et al., Biochemistry 1995;34:4186-4192; Inouye et al., J Struct Biol 1998;122:247-255]. Moreover, in this article we also characterize the diffusion behavior in conformational space, investigating its relations with folding/unfolding conditions. (c) 2005 Wiley-Liss, Inc
Theoretical modeling of the absorption spectrum of aqueous riboflavin
No full textIn this study we report the modeling of the absorption spectrum of riboflavin in water using a hybrid quantum/classical mechanical approach, the MD-PMM methodology. By means of MD-PMM calculations, with which the effect of riboflavin internal motions and of solvent interactions on the spectroscopic properties can be explicitly taken into account, we obtain an absorption spectrum in very good agreement with the experimental spectrum. In particular, the calculated peak maxima show a consistent improvement with respect to previous computational approaches. Moreover, the calculations show that the interaction with the environment may cause a relevant recombination of the gas-phase electronic states
Tuning the low-temperature phase behavior of aqueous ionic liquids
No full textWater's anomalous behavior is often explained using a two-liquid model, where two types of water, high-density liquid (HDL) and low-density liquid (LDL), can be separated via a liquid-liquid phase transition (LLPT) at low temperature. Mixtures of water and the ionic liquid hydrazinium trifluoroacetate were suggested to also show an LLPT but with the advantage that there is no rapid ice crystallization hampering its observation. It remains controversial whether these solutions exhibit an LLPT or are instead associated with complex phase separation phenomena. We here show detailed low-temperature calorimetry and diffraction experiments on aqueous solutions containing hydrazinium trifluoroacetate and other similar ionic liquids, all at a solute mole fraction of x = 0.175. Hydrazinium trifluoroacetate, ammonium trifluoroacetate, ethylammonium trifluoroacetate and hydrazinium pentafluoropropionate all boast exothermic transitions unrelated to crystallization as well as remarkable structural changes upon cooling into the glassy state. We propose a model inspired by micelle formation and decomposition in surfactant solutions, which is complemented by MD simulations and allows rationalizing the rich phase behavior of our mixtures during cooling. The fundamental aspect of the model is the hydrophobic nature of fluorinated anions that enables aggregation, which is reversed upon cooling and culminates in the remarkable exothermic first-order transition observed at low temperature. That is, we assign the first-order transition not to an LLPT but to phase-separations similar to the ones when falling below the Krafft temperature. All other solutions merely show simple vitrification behavior. Still, they exhibit distinct differences in liquid fragility, which is decreased continuously with decreasing hydrophobicity of the anions. This might enable the systematic tuning of ionic liquids with the goal of designing aqueous solutions of specific fragility.The hydrophobic nature of small perfluorinated anions causes aggregation in the liquid and phase-separation upon cooling. The latter is causes an exothermic first-order transition that was previously confused with a liquid-liquid phase transition in water
A statistical mechanical model of supercooled water based on minimal clusters of correlated molecules
Full text linkIn this paper, we apply a theoretical model for fluid state thermodynamics to investigate simulated water in supercooled conditions. This model, which we recently proposed and applied to sub- and super-critical fluid water [Zanetti-Polzi et al., J. Chem. Phys. 156(4), 44506 (2022)], is based on a combination of the moment-generating functions of the enthalpy and volume fluctuations as provided by two gamma distributions and provides the free energy of the system as well as other relevant thermodynamic quantities. The application we make here provides a thermodynamic description of supercooled water fully consistent with that expected by crossing the liquid-liquid Widom line, indicating the presence of two distinct liquid states. In particular, the present model accurately reproduces the Widom line temperatures estimated with other two-state models and well describes the heat capacity anomalies. Differently from previous models, according to our description, a cluster of molecules that extends beyond the first hydration shell is necessary to discriminate between the statistical fluctuation regimes typical of the two liquid states
A general statistical mechanical model for fluid system thermodynamics: Application to sub- and super-critical water
No full textWe propose in this paper a theoretical model for fluid state thermodynamics based on modeling the fluctuation distributions and, hence, the corresponding moment generating functions providing the free energy of the system. Using the relatively simple and physically coherent gamma model for the fluctuation distributions, we obtain a complete theoretical equation of state, also giving insight into the statistical/molecular organization and phase or pseudo-phase transitions occurring under the sub- and super-critical conditions, respectively. Application to sub- and super-critical fluid water and a comparison with the experimental data show that this model provides an accurate description of fluid water thermodynamics, except close to the critical point region where limited but significant deviations from the experimental data occur. We obtain quantitative evidence of the correspondence between the sub- and super-critical thermodynamic behaviors, with the super-critical water pseudo-liquid and pseudo-gas phases being the evolution of the sub-critical water liquid and gas phases, respectively. Remarkably, according to our model, we find that for fluid water the minimal subsystem corresponding to either the liquid-like or the gas-like condition includes an infinite number of molecules in the sub-critical regime (providing the expected singularities due to macroscopic phase transitions) but only five molecules in the super-critical regime (coinciding with the minimal possible hydrogen-bonding cluster), thus suggesting that the super-critical regime be characterized by the coexistence of nanoscopic subsystems in either the pseudo-liquid or the pseudo-gas phase with each subsystem fluctuating between forming and disrupting the minimal hydrogen-bonding network
Early prediction of spinodal-like relaxation events in supercooled liquid water
No full textSeveral computational studies on different water models reported evidence of a phase transition in supercooled conditions between two liquid states of water differing in density: the high-density liquid (HDL) and the low-density liquid (LDL). Yet, conclusive experimental evidence of the existence of a phase transition between the two liquid water phases could not be obtained due to fast crystallization in the region where the phase transition should occur. For the same reason, the investigation of possible transition mechanisms between the two phases is committed to computational investigations. In this work, we simulate an out-of-equilibrium temperature-induced transition from the LDL to the HDL-like state in the TIP4P/2005 water model. To structurally characterize the system relaxation, we use the node total communicability (NTC) we recently proposed as an effective order parameter to discriminate the two liquid phases differing in density. We find that the relaxation process is compatible with a spinodal-like scenario. We observe the formation of HDL-like domains in the LDL phase and we characterize their fluctuating behavior and subsequent coarsening and stabilization. Furthermore, we find that the formation of stable HDL-like domains is favored in the regions where the early formation of small patches of highly connected HDL-like molecules (i.e., with very high NTC values) is observed. Besides characterizing the LDL- to HDL-like relaxation from a structural point of view, these results also show that the NTC order parameter can serve as an early-time predictor of the regions from which the transition process initiates
On the Origin of the Red-Shifted Flavin Absorption Spectra in Fatty Acid Photodecarboxylase
Full text linkFatty acid photodecarboxylase (FAP) is one of the few known natural photoenzymes and has attracted considerable interest due to its ability to convert fatty acids into hydrocarbons upon photoexcitation of its oxidized flavin adenine dinucleotide (FAD) cofactor. Notably, FAD in FAP exhibits an absorption spectrum red-shifted by approximately 10-15 nm compared to many other flavoproteins. This shift might arise from the specific electrostatics of the binding pocket and/or the slightly bent conformation of the FAD, as suggested by the crystallographic data. During the photocycle, an even more red-shifted intermediate (FADRS) has been observed, which ultimately reverts to the original state. In this work, we simulate the absorption spectrum of FAD inside FAP using a hybrid computational approach that combines quantum mechanics (QM) and molecular dynamics (MD) simulations in the Perturbed Matrix Method (PMM) framework. The computed absorption spectrum matches and explains the experimental one, not only validating the effectiveness of the MD-PMM approach but also revealing that the observed red shift primarily originates from the electrostatic environment provided by the protein matrix, whereas the effect of bending is comparatively minor. Additionally, we show that the formation of FAD RS is unrelated to changes in active-site residue protonation or FAD conformation, but instead is likely to arise from a stable interaction between the flavin ring and bicarbonate, one of the proposed reaction products
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