Enhanced connectivity and mobility in liquid water : implications for the high density liquid structure and its onset

In this work, we investigate simulated liquid water at ambient pressure in both stable and metastable supercooled conditions by means of a new order parameter we recently proposed, namely the node total communicability (NTC), based on graph theory concepts. We show that this order parameter is able to identify the two liquid states differing in density, the LDL- and HDL-like states, in simulation conditions at which both states coexist. We also show that NTC is able to capture both the structural and dynamic differences between the two states, being correlated with both the local density and the mobility of water molecules within the network. In addition, we further investigate the high connectivity patches we previously identified as characteristic of the HDL-like states. We show that these extended patches are composed of molecules with an increased local density and mobility, packed in a highly connected network. The formation of these highly connected networks is characterized by a fast dynamics, with mobile molecules entering and exiting the patches. Interestingly, we observe small highly connected patches also at low temperatures, where the prevailing states is LDL-like. We show that the small-to-large patches transition is related to the Widom line crossing and we suggest that the small highly connected patches at low temperatures might function as initial sites for the formation of extended HDL-like regions characteristic of the highest temperatures

A dynamical approach to non-adiabatic electron transfers at the bio-inorganic interface

none2nononeZanetti-Polzi, Laura; Corni, StefanoZanetti Polzi, Laura; Corni, Stefan

Evidence of a Thermodynamic Ramp for Hole Hopping to Protect a Redox Enzyme from Oxidative Damage

Redox proteins and enzymes are at risk of irreversible oxidative damage from highly oxidizing intermediates generated in the active site in the case of unsuccessful functional reaction. Chains of tyrosine and/or tryptophan residues have been recently proposed to provide protection to the active site and the whole protein by delivering oxidizing equivalents (holes) out of the protein via a multistep hopping mechanism. In the present work we use a hybrid quantum/classical theoretical–computational methodology based on the perturbed matrix method and on molecular dynamics simulations to calculate the oxidation potential difference along a chain of tyrosine and tryptophan residues in a human redox enzyme of major importance, a superoxide dismutase, which acts as antioxidant defense. We show that the hole hopping is thermodynamically favored along such a chain and that the hopping propensity is strongly affected by the protein environment and in particular by the active site and its second coordination sphere

Segregation on the nanoscale coupled to liquid water polyamorphism in supercooled aqueous ionic-liquid solution

The most intriguing hypothesis explaining many water anomalies is a metastable liquid-liquid phase transition (LLPT) at high pressure and low temperatures, experimentally hidden by homogeneous nucleation. Recent infrared spectroscopic experiments showed that upon addition of hydrazinium trifluoroacetate to water, the supercooled ionic solution undergoes a sharp, reversible LLPT at ambient pressure, possible offspring of that in pure water. Here, we calculate the temperature-dependent signature of the OH-stretching band, reporting on the low/high density phase of water, in neat water and in the same experimentally investigated ionic solution. The comparison between the infrared signature of the pure liquid and that of the ionic solution can be achieved only computationally, providing insight into the nature of the experimentally observed phase transition and allowing us to investigate the effects of ionic compounds on the high to low density supercooled liquid water transition. We show that the experimentally observed crossover behavior in the ionic solution can be reproduced only if the phase transition between the low- and high-density liquid states of water is coupled to a mixing-unmixing transition between the water component and the ions: at low temperatures, water and ions are separated and the water component is a low density liquid. At high temperatures, water and ions get mixed and the water component is a high-density liquid. The separation at low temperatures into ion-rich and ion-poor regions allows unveiling the polyamorphic nature of liquid water, leading to a crossover behavior resembling that observed in supercooled neat water under high pressure

A general statistical mechanical model for fluid system thermodynamics: application to sub- and super-critical water

We 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

Fully atomistic multiscale approach for pKa prediction

The ionization state of titratable amino acids strongly affects proteins structure and functioning in a large number of biological processes. It is therefore essential to be able to characterize the pKa of ionizable groups inside proteins and to understand its microscopic determinants in order to gain insights into many functional properties of proteins. A big effort has been devoted to the development of theoretical approaches for the prediction of deprotonation free energies, yet the accurate theoretical/computational calculation of pKa values is recognized as a current challenge. A methodology based on a hybrid quantum/classical approach is here proposed for the computation of deprotonation free energies. The method is applied to calculate the pKa of formic acid, methylammonium, and methanethiol, providing results in good agreement with the corresponding experimental estimates. The pKa is also calculated for aspartic acid and lysine as single residues in solution and for three aspartic/glutamic acids inside a well-characterized protein: hen egg white lysozyme. While for small molecules the method is able to deal with multiple protonation states of all titratable groups, this becomes computationally very expensive for proteins. The calculated pKa values for the single amino acids (except for the zwitterionic aspartic acid) and inside the protein display a systematic shift with respect to the experimental values that suggests that the fine balance between hydrophobic and polar interactions might be not accurately reproduced by the usual classical force-fields, thus affecting the computation of deprotonation free energies. The calculated pKa shifts inside the protein are in good agreement with the corresponding experimental ones (within 1 pKa unit), well reproducing the pKa changes due to the protein environment even in the case of large pKa shifts

A statistical mechanical model of supercooled water based on minimal clusters of correlated molecules

In 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

Extending the essential dynamics analysis to investigate molecular properties: application to the redox potential of proteins

Here, a methodology is proposed to investigate the collective fluctuation modes of an arbitrary set of observables, maximally contributing to the fluctuation of another functionally relevant observable. The methodology, based on the analysis of fully classical molecular dynamics (MD) simulations, exploits the essential dynamics (ED) method, originally developed to analyse the collective motions in proteins. We apply this methodology to identify the residues that are more relevant for determining the reduction potential (E(0)) of a redox-active protein. To this aim, the fluctuation modes of the single-residue electrostatic potentials mostly contributing to the fluctuations of the total electrostatic potential (the main determinant of E(0)) are investigated for wild-type azurin and two of its mutants with a higher E(0). By comparing the results here obtained with a previous study on the same systems [Zanetti-Polzi et al., Org. Biomol. Chem., 2015, 13, 11003] we show that the proposed methodology is able to identify the key sites that determine E(0). This information can be used for a general deeper understanding of the molecular mechanisms on the basis of the redox properties of the proteins under investigation, as well as for the rational design of mutants with a higher or lower E(0). From the results of the present analysis we propose a new azurin mutant that, according to our calculations, shows a further increase of E(0)

Surface Packing Determines the Redox Potential Shift of Cytochrome c Adsorbed on Gold

Thermodynamic and dynamic properties of iso-1-cytochrome c covalently bound to a bare gold surface are here investigated by large scale atomistic simulations. The reduction potential of the protein for low and high surface concentrations is calculated showing a good agreement with experimental estimates. The origin of the dependence of the reduction potential on the surface concentration is investigated and is demonstrated to stem from the changing polarizability of the environment surrounding the protein, a mechanism reminiscent of crowding effects. Moreover, structural analyses are performed revealing relevant changes induced by the presence of the electrode on the dynamic properties of cytochrome c. In particular, one of the two cavities previously identified on the protein surface [Bortolotti et al. J. Am. Chem. Soc., 2012, 134, 13670], and that reversibly open in cytochrome c freely diffusing in solution, is found to be deformed when the protein is adsorbed on gold. This modification exemplifies a mechanism that potentially leads to changes in the protein properties by surface-induced modification of its dynamical behavior