Quantum Mechanical Level Research Articles

Temporal coherence of a photon condensate: A quantum trajectory description

In order to study the temporal coherence of a single-mode dye-cavity photon condensate, a model is developed for the dynamics which treats the condensate mode on a quantum-mechanical level. The effects of driving-dissipation and Kerr interactions on the number fluctuations are studied analytically and numerically, including the finding of a long-$\tau$ antibunching effect. Depending on the interaction strength, we quantitatively observe an exponential Schawlow-Townes-like decay or Gaussian Henry-like decay of phase correlations. The adequacy of a heuristic phasor model originating from laser physics in describing number and phase dynamics is validated within the experimentally relevant parameter regime. The ratio of the first and second order coherence times is shown to be inversely proportional to the number fluctuations, with a prefactor that varies smoothly throughout the crossover between canonical and grandcanonical statistics.

Radioactive beams and inverse kinematics: Probing the quantal texture of the nuclear vacuum

The properties of the quantum electrodynamic (QED) vacuum in general, and of the nuclear vacuum (ground) state in particular are determined by virtual processes implying the excitation of a photon and of an electron--positron pair in the first case and of, for example, the excitation of a collective quadrupole surface vibration and a particle--hole pair in the nuclear case. Signals of these processes can be detected in the laboratory in terms of what can be considered a nuclear analogue of Hawking radiation. An analogy which extends to other physical processes involving QED vacuum fluctuations like the Lamb shift, pair creation by $\gamma-$rays, van der Waals forces and the Casimir effect, to the extent that one concentrates on the eventual outcome resulting by forcing a virtual process to become real, and not on the role of the black hole role in defining the event horizon. In the nuclear case, the role of this event is taken over at a microscopic, fully quantum mechanical level, by nuclear probes (reactions) acting on a virtual particle of the zero point fluctuation (ZPF) of the nuclear vacuum in a similar irreversible, no--return, fashion as the event horizon does, letting the other particle, entangled with the first one, escape to infinity, and eventually be detected. With this proviso in mind one can posit that the reactions $^1$H($^{11}$Be,$^{10}$Be$(2^+$;3.37 ${\rm MeV}$))$^2$H and $^{1}$H($^{11}$Li,$^9$Li($1/2^-$; 2.69 ${\rm MeV}$))$^3$H together with the associated $\gamma-$decay processes indicate a possible nuclear analogy of Hawking radiation.

Accurate interaction energies by spin component scaled Möller-Plesset second order perturbation theory calculations with optimized basis sets (SCS-MP2mod): Development and application to aromatic heterocycles.

The Spin Component Scaled (SCS) MP2 method using a reduced and optimized basis set (SCS-MP2mod) is employed to compute the interaction energies of nine homodimers, formed by aromatic heterocyclic molecules (pyrrole, furan, thiophene, oxazole, isoxazole, pyridine, pyridazine, pyrimidine, and pyrazine). The coefficients of the same-spin and opposite-spin correlation energies and the Gaussian type orbitals (GTO) polarization exponents of the 6-31G** basis set are simultaneously optimized in order to minimize the energy differences with respect to the coupled-cluster with single, double and perturbative triples excitations [CCSD(T)] reference interaction energies, extrapolated to a complete basis set. It is demonstrated that the optimization of the spin scale factors leads to a noticeable improvement of the accuracy with a root mean square deviation less than 0.1 kcal/mol and a largest unsigned deviation smaller than 0.25 kcal/mol. The pyrrole dimer provides an exception, with a slightly higher deviation from the reference data. Given the high benefit in terms of computational time with respect to the CCSD(T) technique and the small loss of accuracy, the SCS-MP2mod method appears to be particularly suitable for extensive sampling of intermolecular potential energy surfaces at a quantum mechanical level. Within this framework, a transferability test of the SCS-MP2mod parameters to a benchmark set of this class of molecules is very promising as the reference interaction energies of several heterocyclic aromatic heterodimers were reproduced with a standard deviation of 0.30 kcal/mol. The SCS-MP2mod remarkably outperforms the value of 1.95 kcal/mol obtained with standard MP2/6-31G**.

Vibrational Spectroscopy in Solution through Perturbative ab Initio Molecular Dynamics Simulations.

We have developed a method that allows computing the vibrational spectra at a high quantum mechanical level for molecules in solution or other complex systems. The method is based on the use of configurational samplings from combined QM/MM molecular dynamics simulations and the use of perturbation theory to calculate accurate molecular properties. Such calculations provide in addition accurate free energy gradient vectors and Hessian matrices and thus open the door for the characterization of stationary points in free energy landscapes and the study of chemical reaction mechanisms in large disordered systems. The vibrational spectrum of the water molecule in liquid water has been computed as a test case. It has been obtained using a weighted average of instantaneous signals assuming the instantaneous normal modes approach. Vibrational frequencies are also computed by diagonalizing the Hessian of the free energy surface. Comparison is made with experimental data and with calculations using the Fourier transform of the time autocorrelation function of the dipole moment. The discussion emphasizes the advantages of the developed methodology compared to other techniques in terms of the accuracy/computational cost ratio.

Are Explicit Solvent Models More Accurate than Implicit Solvent Models? A Case Study on the Menschutkin Reaction.

In this work, contemporary quantum mechanical (QM) implicit solvent models (SMD, SM12, and COSMO-RS) and a molecular mechanical (MM) explicit solvent model were used to predict the aqueous free energy barrier of a simple Menschutkin reaction (NH3 + CH3Cl). Surprisingly, the explicit solvent approach performed the worst, while the implicit solvent models yielded reasonably accurate values that are in accord with available experimental data. The origin of the large error in the explicit solvent model was due to the use of a fixed set of Lennard-Jones parameters during the free energy perturbation (FEP) calculations. Further analyses indicate that M06-2X/6-31+G(d,p) yielded solute-solvent interaction energies that are in good agreement with benchmark DLPNO-CCSD(T)/CBS values. When end-state MM to M06-2X/6-31+G(d,p) corrections were added using FEP, it significantly improved the accuracy of the explicit solvent MM result and demonstrated that the accuracy of these models may be systematically improved with end-state corrections based on a validated QM level of theory.

Absence of a spontaneous long-range order in a mixed spin-(1/2, 3/2) Ising model on a decorated square lattice due to anomalous spin frustration driven by a magnetoelastic coupling

The mixed spin-(1/2, 3/2) Ising model on a decorated square lattice, which takes into account lattice vibrations of the spin-3/2 decorating magnetic ions at a quantum-mechanical level under the assumption of a perfect lattice rigidity of the spin-1/2 nodal magnetic ions, is examined via an exact mapping correspondence with the effective spin-1/2 Ising model on a square lattice. Although the considered magnetic structure is in principle unfrustrated due to bipartite nature of a decorated square lattice, the model under investigation may display anomalous spin frustration driven by a magnetoelastic coupling. It turns out that the magnetoelastic coupling is a primary cause for existence of the frustrated antiferromagnetic phases, which exhibit a peculiar coexistence of antiferromagnetic long-range order of the nodal spins with a partial disorder of the decorating spins with possible reentrant critical behavior. Under certain conditions, the anomalous spin frustration caused by the magnetoelastic coupling is responsible for unprecedented absence of spontaneous long-range order in the mixed-spin Ising model composed from half-odd-integer spins only.

Can multiscale simulations unravel the function of metallo-enzymes to improve knowledge-based drug discovery?

Metallo-enzymes are a large class of biomolecules promoting specialized chemical reactions. Quantum-classical quantum mechanics/molecular mechanics molecular dynamics, describing the metal site at quantum mechanics level, while accounting for the rest of system at molecular mechanics level, has an accessible time-scale limited by its computational cost. Hence, it must be integrated with classical molecular dynamics and enhanced sampling simulations to disentangle the functions of metallo-enzymes. In this review, we provide an overview of these computational methods and their capabilities. In particular, we will focus on some systems such as CYP19A1 a Fe-dependent enzyme involved in estrogen biosynthesis, and on Mg2+-dependent DNA/RNA processing enzymes/ribozymes and the spliceosome, a protein-directed ribozyme. This information may guide the discovery of drug-like molecules and genetic manipulation tools.

Ranking Reversible Covalent Drugs: From Free Energy Perturbation to Fragment Docking.

Reversible covalent inhibitors have drawn increasing attention in drug design, as they are likely more potent than noncovalent inhibitors and less toxic than covalent inhibitors. Despite those advantages, the computational prediction of reversible covalent binding presents a formidable challenge because the binding process consists of multiple steps and quantum mechanics (QM) level calculation is needed to estimate the covalent binding free energy. It has been shown that the dissociation rates and the equilibrium dissociation constants vary significantly even with similar warheads, due to noncovalent interactions. We have previously used a simplistic two-state model for predicting the relative binding selectivity of reversible covalent inhibitors ( J. Am. Chem. Soc. 2017, 139 , 17945 ). Here we go beyond binding selectivity and demonstrate that it is possible to use free energy perturbation (FEP) molecular dynamics (MD) to calculate the overall reversible covalent binding using a specially designed thermodynamic cycle. We show that FEP can predict the varying binding free energies of the analogs sharing a common warhead. More importantly, our results revealed that the chemical modification away from warhead alters the binding affinity at both noncovalent and covalent binding states, and the computational prediction can be improved by considering the binding free energy of both states. Furthermore, we explored the possibility of using a more rapid computational method, site-identification by ligand competitive saturation (SILCS), to rank the same set of reversible covalent inhibitors. We found that the fragment docking to a set of precomputed fragment maps produces a reasonable ranking. In conclusion, two independent approaches provided consistent results that the covalent binding state is suitable for the initial ranking of the reversible covalent drug candidates. For lead-optimization, the FEP approach designed here can provide more rigorous and detailed information regarding how much the covalent and noncovalent binding states are contributing to the overall binding affinity, thus offering a new avenue for fine-tuning the noncovalent interactions for optimizing reversible covalent drugs.

Enthalpy-Entropy Interplay in π-Stacking Interaction of Benzene Dimer in Water.

Aromatic groups can engage in an interesting class of noncovalent interactions termed π-π interactions, which play a pivotal role in stabilizing a variety of molecular architectures, including nucleic acids, proteins, and supramolecular assemblies. When the aromatic compounds interact with each other in an aqueous environment, their association is facilitated by the hydrophobic effect-the trend of nonpolar solutes to aggregate in a polar solution. To develop an in-depth understanding of hydrophobic association, we investigate in the present work π-π interactions in water, employing as a paradigm the benzene dimer. Using DFT-CES, a mean-field QM/MM method recently developed by our group, we describe the benzene solute at a quantum-mechanical level. Full consideration of detailed solute-electron density enables an optimal description of the solute-solvent interactions, leading to an accurate prediction of hydration free energies. In π-stacking of benzene, we find an entropic stabilization associated with the shrinkage of the solvent-excluded volume, which agrees with the theory of hydrophobic effect at subnanoscales. However, at the equilibrium binding distance of the benzene dimer, we find that the entropic stabilization nearly cancels out due to the enthalpic cost required for dewetting the internal space. Such an enthalpy-entropy compensation leads the association free energy to be predominantly dictated by the solute-solute interaction enthalpy. The present work offers new insight into the mechanistic role of water and the primary thermodynamic driving force of hydrophobic association.

BAR-based multi-dimensional nonequilibrium pulling for indirect construction of QM/MM free energy landscapes: from semi-empirical to ab initio

The indirect method for the construction of quantum mechanics (QM)/molecular mechanics (MM) free energy landscapes provides a cheaper alternative for free energy simulations at the QM level. The indirect method features a direct calculation of the free energy profile with a computationally efficient but less accurate Hamiltonian (i.e. low-level Hamiltonian) and a low-level-to-high-level correction. In the thermodynamic cycle, the direct low-level calculation along the physically meaningful reaction coordinate is corrected via the alchemical method, which is often achieved with perturbation-based techniques. In our previous work, a multi-dimensional nonequilibrium pulling framework is proposed for the indirect construction of QM/MM free energy landscapes. Previously, we focused on obtaining semi-empirical QM (SQM) results indirectly from direct MM simulations and MM to SQM corrections. In this work, we apply this method to obtain results under ab initio QM Hamiltonians by combining direct SQM results and SQM to QM corrections. A series of SQM and QM Hamiltonians are benchmarked. It is observed that PM6 achieves the best performance among the low-level Hamiltonians. Therefore, we recommend using PM6 as the low-level theory in the indirect free energy simulation. Considering its higher similarity to the high-level Hamiltonians, PM6 corrected with the bond charge correction could be more accurate than the existing AM1-BCC model. Another central result in the current work is a basic protocol of choosing the strength of restraints and an appropriate time step in nonequilibrium free energy simulation at the stiff spring limit. We provide theoretical derivations to emphasize the importance of using a sufficiently large force constant and choosing an appropriate time step. It is worth noting that a general rule of thumb for choosing the time step, according to our derivation, is that a time step of 1 fs or smaller should be used, as long as the stiff spring approximation is employed, even in simulations with constraints on bonds involving hydrogen atoms.

BAR-based multi-dimensional nonequilibrium pulling for indirect construction of a QM/MM free energy landscape.

Construction of free energy landscapes at the quantum mechanics (QM) level is computationally demanding. As shown in previous studies, by employing an indirect scheme (i.e. constructing a thermodynamic cycle connecting QM states via an alchemical pathway), simulations are converged with much less computational burden. The indirect scheme makes QM/molecular mechanics (MM) free energy simulation orders of magnitude faster than the direct QM/MM schemes. However, the indirect QM/MM simulations were mostly equilibrium sampling based and the nonequilibrium methods were merely exploited in one-dimensional alchemical QM/MM end-state correction at two end states. In this work, we represent a multi-dimensional nonequilibrium pulling scheme for indirect QM/MM free energy simulations, where the whole free energy simulation is performed only with nonequilibrium methods. The collective variable (CV) space we explore is a combination of one alchemical CV and one physically meaningful CV. The current nonequilibrium indirect QM/MM simulation method can be seen as the generalization of equilibrium perturbation based indirect QM/MM methods. The test systems include one backbone dihedral case and one distance case. The two cases are significantly different in size, enabling us to investigate the dependence of the speedup of the indirect scheme on the size of the system. It is shown that the speedup becomes larger when the size of the system becomes larger, which is consistent with the scaling behavior of QM Hamiltonians.

Binding and Catalytic Mechanisms of Veratryl Alcohol Oxidation by Lignin Peroxidase: A Theoretical and Experimental Study

Lignin peroxidase (LiP) and its natural substrate veratryl alcohol (VA) play a crucial role in lignin degradation by white-rot fungi. Understanding the molecular determinants for the interaction of this enzyme with its substrates is essential in the rational design of engineered peroxidases for biotechnological application. Here, we combine computational and experimental approaches to analyze the interaction of Phanerochaete chrysosporium LiP (isoenzyme H8) with VA and its radical cation (VA•+, resulting from substrate oxidation by the enzyme). Interaction energy calculations at semiempirical quantum mechanical level (SQM) between LiP and VA/VA•+ enabled to identify those residues at the acidic environment of catalytic Trp171 involved in the main interactions. Then, a battery of variants, with single and multiple mutations at these residues (Glu168, Asp165, Glu250, Asp264, and Phe267), was generated by directed mutagenesis, and their kinetics parameters were estimated on VA and two additional substrates. The experimental results show that Glu168 and Glu250 are crucial for the binding of VA, with Glu250 also contributing to the turnover of the enzyme. The experimental results were further rationalized through new calculations of interaction energies between VA/VA•+ and LiP with each of the single mutations. Finally, the delocalization of spin density was determined with quantum mechanics/molecular mechanics calculations (QM/MM), further supporting the contribution of Glu250 to VA oxidation at Trp171.

Studies on computational chemistry and complexation behavior between Poly(styrene-co-methacrylic acid) and Poly(styrene-co-4-vinylpyridine)

Computational approaches plays a dynamic role in the variety of modules for quantum mechanical (QM) and molecular mechanical (MM) simulations by 09 software. In this work complexation behavior has been investigated between different composition of poly styrene-co-methacrylic acid (SMA) and poly styrene-co-4-vinylpyridine (S4VP). Polymer-polymer complexations performed by semi-empirical methods are DFT (B3LYP,RHF) levels of theory via 6-31 basis set. Quantitative interaction analyzed by different techniques such as optimization of conformers, binding energy of blend polymers through Hartree-Fock (HF), hydrogen non-polar bond distance, spectrum of IR/UV-Vis spectroscopy at MM & QM model, and the excitation energy at quantum mechanical level change into wavelength contains a number of absorption bands (200, 261.17, 250, 300, 350 nm). In this research an impact on miscibility complexation was also observed in polymers blend system followed by hydrogen-bonding SMA and S4VP (QM = 6.40, MM = 17.25). This research further confirmed the Hydrogen-bonding connections between carboxylic and pyridine clusters in different areas (MM = 3200 , QM = 3400 ) by a qualitative analysis through IR. Furthermore it is observed that QM methods provide distinct data as compared to MM methods, however it is worth mentioning that QM methods produce more reliable data of different properties of the system.

GPU Accelerated Quantum Virtual Screening: Application for the Natural Inhibitors of New Dehli Metalloprotein (NDM-1).

Quantum mechanical approaches for the massive computation on large biological system such as virtual screening in drug design and development have presented a challenge to computational chemists for many years. In this study, we demonstrated that by taking advantage of rapid growth of GPU-based hardware and software (i.e., teraChem), it is feasible to perform virtual screening of a refined chemical library at quantum mechanical level in order to identify the lead compounds with improved accuracy, especially for the drug targets such as metalloproteins in which significant charge transfer and polarization occur amongst the metal ions and their coordinated amino acids. Our calculations predicted four nature compounds (i.e., Curcumin, Catechin, menthol, and Ferulic acid) as the suitable inhibitors for antibiotics resistance against New Delhi Metallo-β-lactamase-1 (NDM-1). Molecular orbitals (MOs) of the QM region of metal ions and their coordinated residues indicate that the bridged hydroxide ion delocalized the electron over the Zn-OH-Zn group at HOMO, different from MOs when the OH− is not presented in NDM-1. This indicates that the bridged hydroxide ion plays an important role in the design of antibiotics and other inhibitors targeting the metalloproteins.

Hydrogen, boron and nitrogen atoms in diamond: a quantum mechanical vibrational analysis

The structural, electronic and vibrational properties of two common defects in diamond, CHN and CHB, describing the case in which a carbon C1 atom is substituted by a nitrogen atom, or by a boron atom, breaking a C1–C2 bond, followed by the saturation of the dangling bond of C2 by a hydrogen atom, are investigated at the quantum mechanical level, by using a periodic supercell approach, hybrid DFT functionals and a local Gaussian-type basis set as implemented in the CRYSTAL code. The effect of concentration of the defects has been explored, by considering two supercells containing 64 and 216 atoms (S64 and S216). Formation and hydrogenation energies, geometries, Mulliken charges and the band structure of both defects are reported. The vibrational features of the defects have been investigated, by generating the IR and Raman spectra, and by analyzing graphically and through the isotopic substitution (H → D, 11B → 10B and 14N → 15N) the nature of the most relevant modes related to the defects. The computed C–H stretching mode of CHN, once corrected for anharmonicity (3408 cm $$^{-1}$$ ), falls to wavenumbers very close to the experimental peak observed at 3394 cm $$^{-1}$$ , which can then be reasonably attributed to this specific defect. The present manuscript is included in a special volume in honor and memory of Janos Angyan. Although he did not study in particular the kind of defects discussed in the present manuscript, the many methodological contributions he introduced in computational science have inspired many of the tools we have been using here. One of the present authors, RD, in particular, is grateful to Janos for the illuminating discussions they had in Paris, Nancy and Torino.

An average stochastic approach to two-body dissipation in finite fermion systems

We present average stochastic time-dependent Hartree–Fock (ASTDHF) as a theory for efficient handling of incoherent dynamical correlations in finite fermion systems at fully quantum-mechanical level. The basic time evolution is given by time-dependent mean-field theory. The two-body collisions beyond mean-field propagation are evaluated stochastically in an incoherent ensemble of mean-field states as was done in the previously developed STDHF. The new, and time saving, feature in ASTDHF is that it employs one common mean field throughout the whole ensemble. A detailed presentation of ASTDHF is given and extensive comparison with STDHF and other approaches to dissipation are discussed. ASTDHF is found to be a very efficient approach for well bound systems where mean-field fluctuations remain small.

Probing vibrational coupling via a grid-based quantum approach-an efficient strategy for accurate calculations of localized normal modes in solid-state systems.

In this work an approach to investigate the properties of strongly localized vibrational modes of functional groups in bulk material and on solid‐state surfaces is presented. The associated normal mode vectors are approximated solely on the basis of structural information and obtained via diagonalization of a reduced Hessian. The grid‐based Numerov procedure in one and two dimensions is then applied to an adequate scan of the respective potential surface yielding the associated vibrational wave functions and energy eigenvalues. This not only provides a detailed description of anharmonic effects but also an accurate inclusion of the coupling between the investigated vibrational states on a quantum mechanical level. All results obtained for the constructed normal modes are benchmarked against their analytical counterparts obtained from the diagonalization of the total Hessian of the entire system. Three increasingly complex systems treated at quantum chemical level of theory have been considered, namely the symmetric and asymmetric stretch vibrations of an isolated water molecule, hydroxyl groups bound to the surface of GeO2 (001), ‐quartz(001) and Rutil (001) as well as crystalline Li2NH serving as an example for a bulk material. While the data obtained for the individual systems verify the applicability of the proposed methodology, comparison to experimental data demonstrates the accuracy of this methodology despite the restriction to limit this methodology to a few selected vibrational modes.The possibility to investigate vibrational phenomena of localized normal modes without the requirement of executing costly harmonic frequency calculations of the entire system enables the application of this method to cases in which the determination of normal modes is prohibitively expensive or not available for a particular level of theory. © 2018 Wiley Periodicals, Inc.

Anomalous Breaking of Scale Invariance in a Two-Dimensional Fermi Gas.

The frequency of the breathing mode of a two-dimensional Fermi gas with zero-range interactions in a harmonic confinement is fixed by the scale invariance of the Hamiltonian. Scale invariance is broken in the quantized theory by introducing the two-dimensional scattering length as a regulator. This is an example of a quantum anomaly in the field of ultracold atoms and leads to a shift of the frequency of the collective breathing mode of the cloud. In this work, we study this anomalous frequency shift for a two-component Fermi gas in the strongly interacting regime. We measure significant upwards shifts away from the scale-invariant result that show a strong interaction dependence. This observation implies that scale invariance is broken anomalously in the strongly interacting two-dimensional Fermi gas.

Binding free energies in the SAMPL6 octa-acid host\u2013guest challenge calculated with MM and QM methods

We have estimated free energies for the binding of eight carboxylate ligands to two variants of the octa-acid deep-cavity host in the SAMPL6 blind-test challenge (with or without endo methyl groups on the four upper-rim benzoate groups, OAM and OAH, respectively). We employed free-energy perturbation (FEP) for relative binding energies at the molecular mechanics (MM) and the combined quantum mechanical (QM) and MM (QM/MM) levels, the latter obtained with the reference-potential approach with QM/MM sampling for the MM → QM/MM FEP. The semiempirical QM method PM6-DH+ was employed for the ligand in the latter calculations. Moreover, binding free energies were also estimated from QM/MM optimised structures, combined with COSMO-RS estimates of the solvation energy and thermostatistical corrections from MM frequencies. They were performed at the PM6-DH+ level of theory with the full host and guest molecule in the QM system (and also four water molecules in the geometry optimisations) for 10–20 snapshots from molecular dynamics simulations of the complex. Finally, the structure with the lowest free energy was recalculated using the dispersion-corrected density-functional theory method TPSS-D3, for both the structure and the energy. The two FEP approaches gave similar results (PM6-DH+/MM slightly better for OAM), which were among the five submissions with the best performance in the challenge and gave the best results without any fit to data from the SAMPL5 challenge, with mean absolute deviations (MAD) of 2.4–5.2 kJ/mol and a correlation coefficient (R2) of 0.77–0.93. This is the first time QM/MM approaches give binding free energies that are competitive to those obtained with MM for the octa-acid host. The QM/MM-optimised structures gave somewhat worse performance (MAD = 3–8 kJ/mol and R2 = 0.1–0.9), but the results were improved compared to previous studies of this system with similar methods.

GPx4 is the controller of a specific form of programmed cell death executed by lipid peroxidation products

The recent identification of a routine of non-apoptotic controlled cell death recapitulates in a physiological perspective the long history of oxygen toxicity and lipid peroxidation. Due to the critical role of iron, this form of controlled non-apoptotic cell death had been named ferroptosis1. Ferroptosis executes cell death in major neurodegenerative diseases and ischemia-reoxygenation and accounts for of cytotoxicity of drug candidates for cancer treatment2. Moreover, evidence on embryo development indicates that ferroptosis is also involved in tissue homeostasis3. What we know is that oxygen, phospholipids containing ω-6 fatty acids, iron and a lipoxygenase active on membrane lipids are required. We also know that ferroptosis can only be executed by inactivation the selenoperoxidase GPx44. The reduction to hydroperoxy derivatives of lipid hydroperoxides inserted in membranes is, indeed, the critical anti-peroxidant reaction5. Seemingly, in the emerging scenario, oxygen metabolically activated in mitochondria, slowly but continuously generates species competent for free radical oxidation of a polyunsaturated fatty acid, evolving into a lipid hydroperoxide. This activates a lipoxygenase active on membrane lipids to produce more hydroperoxides. By decomposition of lipid hydroperoxides, iron propagates chain reactions and generates the electrophiles (aldehydes?) alleged executing cell death. All these events can only, take place when the reaction of GPx4 becomes limiting. The mechanism of GPx4 reaction has been analyzed up to quantum-mechanical level and calculated structures have been corroborated by MS6. The interaction of GPx4 with membrane phospholipid has been elucidated by Surface Plasmon Resonance (SPR), supported by molecular dynamics (MD) analysis. We know now how GPx4 works on membranes. A strong electrostatic interaction takes place between specific amino acid residues in the cationic area on the surface of GPx4 and polar head of phospholipids. This binding drives the orientation of the hydroperoxidic group flipping out of the membrane to precisely interact with the redox center of the enzyme7. Redox catalysis is operated by proton tunneling leading to the formation of a charge-separated species6. Interaction of the oxidized selenium with two GSH molecules reacting in sequence lessens the interaction with polar head of phospholipids and permits the “surfing” of the enzyme on the membrane surface to catch and reduce lipid hydroperoxides7. In conclusion, metabolism of oxygen in mitochondria provides metabolic energy but can also kill the cells when not sufficiently protected by GPx4 and GSH. About the mechanisms of induction of ferroptosis under physiological conditions we know that GSH concentration can be controlled by the efficiency of the import of cystine for the synthesis of GSH. What is still largely unknown, instead, is how expression/activity of GPx4 could be controlled under physiological conditions.