The Journal of Chemical Physics

Studying the kinetics of long-timescale rare events is a fundamental challenge in molecular simulation. To address this problem, we propose an integration of two different rare-event sampling philosophies: biased enhanced sampling and unbiased path sampling. Enhanced sampling methods, e.g., metadynamics, can facilitate the crossing of free energy barriers by applying an external bias potential. On the contrary, path sampling methods like weighted ensemble do not apply any biasing force but accelerate the exploration of rugged free energy surfaces through trajectory resampling. We show that a judicious combination of the weighted ensemble with a metadynamics-like algorithm can synergize the strengths and mitigate the deficiencies of path sampling and enhanced sampling approaches. The resulting integrated sampling (IS) algorithm improves the computational efficiency of calculating the kinetics of peptide conformational transitions, protein unfolding, and the dissociation of a ligand–receptor complex. Furthermore, the IS approach can direct sampling along the minimum free energy pathway even when the collective variable used for biasing is suboptimal. These advantages make the IS algorithm suitable for studying the kinetics of complex molecular systems of biological and pharmaceutical relevance.

We present an inference scheme of long timescale, non-exponential kinetics from molecular dynamics simulations accelerated by stochastic resetting. Standard simulations provide valuable insight into chemical processes but are limited to timescales shorter than ∼1μs. Slower processes require the use of enhanced sampling methods to expedite them and inference schemes to obtain the unbiased kinetics. However, most kinetics inference schemes assume an underlying exponential first-passage time distribution and are inappropriate for other distributions, e.g., with a power-law decay. We propose an inference scheme that is designed for such cases, based on simulations enhanced by stochastic resetting. We show that resetting promotes enhanced sampling of the first-passage time distribution at short timescales but often also provides sufficient information to estimate the long-time asymptotics, which allows the kinetics inference. We apply our method to a model system and a peptide in an explicit solvent, successfully estimating the unbiased mean first-passage time while accelerating the sampling by more than an order of magnitude.

GW and Bethe–Salpeter equation (BSE) methods are used to calculate energies of excited states of organic molecules in the Quest-3 database [Loos et al., J. Chem. Theory Comput. 16, 1711 (2020)]. The self-energy in the GW approximation is conventionally calculated using the RPA polarizability. Inclusion of a screened electron–hole interaction in the polarizability was recently shown to improve predictions of experimental ionization energies in organic molecules [C. H. Patterson, J. Chem. Theory Comput. 20, 7479 (2024)]. Self-energies from RPA or screened time-dependent Hartree–Fock (TDHF) polarizabilities in the GW/BSE method are used to calculate 141 singlet excited states in Quest-3. Theoretical best estimate excited state energies from the CC3 coupled cluster method and aug-cc-pVTZ basis sets are used to benchmark GW/BSE and CIS calculations using the same molecular geometries and basis sets. Differences between GW/BSE or CIS excited state energies and best estimate values show that there are systematic variations in the accuracies of excited state energies classified as ππ*, nπ*, πR (Rydberg), or nR character. The origin of these variations is the accuracy of self-energies of states of nonbonding vs π bonding character. In particular, N or O lone pair states require large self-energy corrections owing to strong orbital relaxation in the localized hole state, while π states have smaller corrections. Self-energies from a screened TDHF vs RPA polarizability are typically over(under)estimated for nonbonding states, leading to under(over)estimation of energies of excited states of nπ* or nR character.

An integral procedure in every coherent multidimensional spectroscopy experiment is to suppress undesired background signals. For that purpose, one can employ a particular phase-matching geometry or phase cycling, a procedure that was adapted from nuclear magnetic resonance (NMR) spectroscopy. In optical multidimensional spectroscopy, phase cycling has been usually carried out in a “nested” fashion, where pulse phases are incremented sequentially with linearly spaced increments. Another phase-cycling approach that was developed for NMR spectroscopy is “cogwheel phase cycling,” where all pulse phases are varied simultaneously in increments defined by so-called “winding numbers.” Here we explore the concept of cogwheel phase cycling in the context of population-based coherent multidimensional spectroscopy. We derive selection rules for resolving and extracting fourth-order and higher-order nonlinear signals by cogwheel phase cycling and describe how to perform a numerical search for the winding numbers for various population-detected 2D spectroscopy experiments. We also provide an expression for a numerical search for nested phase-cycling schemes and predict the most economical schemes of both approaches for a wide range of nonlinear signals. The signal selectivity of the technique is demonstrated experimentally by acquiring rephasing and nonrephasing fourth-order signals of a laser dye by both phase-cycling approaches. We find that individual nonlinear signal contributions are, in most cases, captured with fewer steps by cogwheel phase cycling compared to nested phase cycling.

In this study, we present a novel orientation discretization approach based on the rhombic triacontahedron for Monte Carlo simulations of semiflexible polymer chains, aiming at enhancing structural analysis through rheo-small-angle scattering (rheo-SAS). Our approach provides a more accurate representation of the geometric features of semiflexible chains under deformation, surpassing the capabilities of traditional lattice structures. Validation against the Kratky–Porod chain system demonstrated superior consistency, underscoring its potential to significantly improve the precision of uncovering geometric details from rheo-SAS data. This approach opens new avenues for investigating the conformations of semiflexible polymers and mechanically induced phase transitions in more complex polymer structures, offering deeper insights into their behavior under various conditions.

The dielectric function of a dipolar liquid exhibits a strong wavenumber dependence in the bulk homogeneous state. Such a behavior seems to suggest the possibility of a strong system size dependence of the dielectric constant (DC) of a nanoconfined liquid, although details have been revealed only recently. The dielectric properties of nanoconfined water, indeed, show a marked sensitivity not only to the size and shape (dielectric boundaries) of confinement but also to the nature of surface–water interactions. For geometries widely studied, namely, water confined in a narrow slit, nanocylinder, and nanospherical cavity, the asymptotic approach to the bulk value of the DC with the increase in confinement size is found to be surprisingly slow. This seems to imply the appearance of a dipolar cross correlation length, much larger than the molecular length-scale of water. In narrow slits and narrow cylinders, the dielectric function becomes both inhomogeneous and anisotropic, and the longitudinal and transverse components display markedly different system size dependencies. This sensitivity can be traced back to the dependence of the DC on the ratio of the mean square dipole moment fluctuation to the volume of the system. The observed sensitivity of collective dipole moment fluctuations to the length scale of confinement points to the possibility of using DC to estimate the orientational correlation length scale, which has been an elusive quantity. Furthermore, the determination of volume also requires special consideration when the system size is in nanoscale. We discuss these and several other interesting issues along with several applications that have emerged in recent years.

The Madrid-2019 force field was recently developed to perform simulations of electrolytes in water. The model was specifically parameterized for TIP4P/2005 water and uses scaled charges for the ions. In this work, we test the compatibility of the Madrid-2019 force field with another water model: TIP4P/Ice. We shall denote this combination as Madrid-2019(TIP4P/Ice) force field. The key idea of this combination is to keep the ion–ion (Madrid-2019) and water–water (TIP4P/Ice) interactions unaltered with respect to the original models and taking the Lennard-Jones parameters for the ion–water interactions from the Madrid-2019 force field. By implementing this approach, we have maintained a reasonably good performance of the model regarding the densities and structural features of aqueous solutions, albeit yielding a moderately higher viscosity than the original model. However, the standout achievement of this new combination lies in its effective reproduction of the absolute values of the freezing temperatures of a number of ionic aqueous solutions, which could also be useful when studying hydrate formation from a two-phase system containing an aqueous solution in contact with a gas.

Using ion–ion coincidence measurements, we experimentally investigate the dissociative triple ionization of argon dimers in relative phase controlled elliptically polarized two-color femtosecond laser fields. By examining the kinetic energy release-dependent momentum angular distribution of the ejected ionic fragments, two distinct pathways, each associated with different intermediates, are identified. Control over the emission directions of the ionic fragments is achieved by varying the relative phase of the elliptical two-color laser fields. Notably, the two pathways exhibit nearly opposite asymmetries in their dependence on the relative phase. Our findings demonstrate the critical role of intermediates in the dissociative triple ionization of dimers and provide a method to distinguish the intermediates involved in this process.

We show that the exact universal density functional of integer electronic charge leads to an extension to fractional charge in an asymptotic sense when it is applied to a system made of asymptotically separated densities. The extended functional is asymptotically local and is said to be i-local. The concept of i-locality is also applicable to nuclear external potentials, and a natural association exists between the localities of a density and a set of nuclei. Applying the functional to a system with nuclei distributed in two asymptotically separated locales requires an explicit search of the electronic charge at each locale with the constraint of the global charge. The determined number of electrons at each locale can be fractional. The molecular size consistency principle is realized as the result of the search. It is physically sensible to extend the molecule concept to include a fractional number of electrons (called fractional molecule henceforth) as a localized observable. The physical validity of fractional molecules is equivalent to the asymptotic separability of molecules, a basic assumption in molecular research. A one-to-one mapping between a fractional molecule’s density and external potential is shown to exist with a nondegenerate condition. The global one-to-one mapping required by the Hohenberg–Kohn first theorem is realized through the aforementioned global search for molecular charges. Furthermore, the well-known piecewise linearity of the universal functional with respect to the number of electrons is necessary for an approximate i-local universal functional to be broadly accurate for any integer number of electrons. The Kohn–Sham (KS) noninteracting kinetic energy functional for a fractional molecule is well-defined and has the same form as that for a system of an integer number of electrons. It is shown to be i-local. A nondegenerate, noninteracting ensemble v-representable fractional density is simultaneously noninteracting wavefunction representable. A constrained search over those representing wavefunctions yields the definition of an exchange–correlation functional pertaining to fractional occupancies of KS orbitals. The functional is shown to be an upper bound to the formal KS exchange–correlation energy of a fractional molecule and includes a strong correlation. It yields the correct result for a well-designed example of effective fractional occupancies in the literature.

A benchmark model that combines an embedded-cluster approach for ionic surfaces with wavefunction-based methods to predict the vibrational frequencies of molecules adsorbed on surfaces is presented. As a representative case, the adsorption of CO on the lowest index non-polar and most stable facet of CeO2, that is, (111) was studied. The CO harmonic vibrational frequencies were not scaled semiempirically but explicitly corrected for anharmonic effects, which amount to about 25 cm−1 with all tested methods. The second-order Møller–Plesset perturbation method (MP2) tends to underestimate the CO harmonic frequency by about 40–45 cm−1 in comparison with the results obtained with the coupled-cluster singles and doubles with perturbational treatment of triple excitation method [CCSD(T)] and independently from the basis set used. The best estimate for the CO vibrational frequency (low-coverage case) differs by 12 cm−1 with the experimental value obtained by infrared reflexion absorption spectroscopy of 1 monolayer CO adsorbed on the oxidized CeO2(111) surface. In addition, a conservative estimate of the adsorption energy of about −0.22 ± −0.07 eV obtained at the CCSD(T) level confirms the physisorption character of the adsorption of CO on the CeO2(111) surface.

Vibrational wave packets are created in the lowest triplet state 13Σu+ of K2 and Rb2 residing on the surface of helium nanodroplets, through non-resonant stimulated impulsive Raman scattering induced by a moderately intense near-infrared laser pulse. A delayed, intense 50-fs laser pulse doubly ionizes the alkali dimers via multiphoton absorption and thereby causes them to Coulomb explode into a pair of alkali ions Ak⁺. From the kinetic energy distribution P(Ekin) of the Ak⁺ fragment ions, measured at a large number of delays, we determine the time-dependent internuclear distribution P(R, t), which represents the modulus square of the wave packet within the accuracy of the experiment. For both K2 and Rb2, P(R, t) exhibits a periodic oscillatory structure throughout the respective 300 and 100 ps observation times. The oscillatory structure is reflected in the time-dependent mean value of R, ⟨R⟩(t). The Fourier transformation of ⟨R⟩(t) shows that the wave packets are composed mainly of the vibrational ground state and the first excited vibrational state, in agreement with numerical simulations. In the case of K2, the oscillations are observed for 300 ps, corresponding to more than 180 vibrational periods with an amplitude that decreases gradually from 0.035 to 0.020 Å. Using time-resolved spectral analysis, we find that the decay time of the amplitude is ∼260 ps. The decrease is ascribed to the weak coupling between the vibrating dimers and the droplet.

Time-dependent density functional theory was employed to investigate the electron dynamics of MoS2 following femtosecond pulse irradiation. The study concerned the effects of laser wavelength, intensities, and polarization and elucidated the ionization mechanisms across the intensity range of 10¹⁰–10¹⁴ W/cm². As laser intensity increases, MoS2 irradiated with an infrared (IR) laser (800 nm) deviates from single-photon absorption at lower intensities compared to that subjected to an ultraviolet (UV) laser (266 nm), and nonlinear effects in the current arise at lower intensities for the 800 nm laser. At a wavelength of 266 nm, MoS2 irradiated with an a-axis polarized laser deposited more energy and generated more electron–hole pairs compared to c-axis polarization. Rate equations were used to estimate the total number of excited electrons in MoS2 and the corresponding plasma frequency. Simulation results indicate that the damage threshold of the UV laser is higher than that of the IR laser, which contradicts the experimental results. This outcome suggests that the mechanism of material damage induced by the UV femtosecond laser near the damage threshold is independent of optical breakdown. The findings of this research are significant for enhancing the performance of MoS2-based photodetectors and optimizing their stability and reliability in high-power, short-wavelength laser applications.

Reactions and interactions at interfaces play pivotal roles in processes ranging from atmospheric aerosols influencing climate to battery electrodes determining charge–discharge rates to defects in catalysts controlling the fate of reactants to the outcome of biological processes at membrane interfaces. Tools to probe these surfaces at the atomic-molecular level are thus critical. Chief among non-invasive probes is the vibrational spectroscopy sum frequency generation (SFG). The complex signal amplitude generated by SFG requires techniques to interfere the unknown amplitude with a well-characterized one. An interferometric method is described to characterize the signal from any nonresonant reference material. The technique is demonstrated by measuring the phase of polycrystalline GaAs, chosen due to the strong signal and insensitivity to surface contamination. With a 515 nm visible field, the phase of GaAs is 54.5° ± 0.5°. The capability of choosing a reference based solely on its signal intensity enables probing a wide range of interfaces.

In this paper, we develop a model based on a second quantization—with anharmonic phonon scattering and the phonon Boltzmann transport equation—to study precise high-resolution nonequilibrium vibrational energy transfer (VET) under selective phonon excitation in cyclotrimethylene trinitramine. We simulate mid-infrared pump–probe spectroscopy and observe a prompt appearance (<1 ps) of broad-spectrum intensity, which agrees well with experimental data in the literature. The selective excitation of phonons at different frequencies reveals distinct VET pathways and the kinetic evolution of mode occupations as the system reaches a new equilibrium temperature. Three types of transition mechanisms are found to play outsized roles in terms of the amount of energy transferred and the transfer rate: (1) vibrational modes close to the excited frequencies typically respond faster and reach higher temperatures regardless of the excitation frequency; (2) the overtone pathway connecting the modes near 550 and 1150 cm⁻¹ is an important bridge between far- and mid-IR; and (3) fast aggregation of energy at 2800 cm⁻¹ mediates transfer to/from high frequencies through a second overtone pathway involving modes near 1400 cm⁻¹. In addition, by monitoring the temperature of the N–N/N–O stretching modes, strong coupling between those modes and the C–H stretching modes is found. The coupling likely draws the vibrational modes close to both the proton transfer transition state for HONO elimination and the N–N stretching for bond cleavage. The high-resolution understanding of the nonequilibrium kinetics of phonons provides important insight into the energy transfer and initiation mechanisms of molecular solids due to external stimuli.

This study presents an ITO/ZnO/ITO/Si memristor fabricated via reactive sputtering for use in advanced analog synaptic plasticity and reservoir computing (RC) systems. The proposed device exhibited stable threshold and nonvolatile switching characteristics by effectively controlling the current compliance (ICC) limit. Multilevel data storage was achieved through controlled multistate switching via reset-stop voltage and ICC. X-ray diffraction analysis confirmed the formation of a polycrystalline ZnO film with a 12:8 oxygen-to-argon ratio, which facilitated the generation of oxygen-vacancy conductive filaments. The memristor effectively replicated key synaptic characteristics such as long-term potentiation, long-term depression, spike-amplitude/width-dependent plasticity, spike-rate-dependent plasticity, and the transition from short-term to long-term memory. The RC system processed binary 4-bit codes and recognized different digits, achieving 98.84% accuracy in handwritten digit recognition using a convolutional neural network simulation, highlighting its potential for efficient image processing applications.

The difference and similarity between the velocity- and position-Verlet integrators are discussed from the viewpoint of their Hamiltonian representations for both linear and nonlinear systems. For a harmonic oscillator, the exact Hamiltonians reveal that positional trajectories generated by the two integrators follow an identical second-order differential equation and thus can be matched by adjusting initial conditions. In contrast, the series expansion of the Hamiltonians for the nonlinear discrete dynamics clearly indicates that the two integrators differ fundamentally. These analytical results are confirmed by simple numerical simulations of harmonic and anharmonic oscillators.

The binding mean spherical approximation theory is used to describe the thermodynamic properties of dicarboxylic acid salts by adding a chain term in the free energy. The dianions in these solutions are modeled as flexible charged chains composed of two, three, or four spheres. Five aqueous solutions of such salts are studied in different concentration ranges: dipotassium oxalate, disodium malonate, disodium succinate, potassium tartrate, and sodium tartrate. A description of the experimental deviations from ideality (osmotic and activity coefficients) for these salts is obtained. The model is compared with a previous one that does not include a chain contribution. It is found that the model with a chain contribution provides a more physically sound framework.

Many ternary mixtures composed of saturated and unsaturated lipids with cholesterol (Chol) exhibit a region of coexistence between liquid-disordered (Ld) and liquid-ordered (Lo) domains, bearing some similarities to lipid rafts in biological membranes. However, biological rafts also contain many proteins that interact with the lipids and modify the distribution of lipids. Here, we extend a previously published lattice model of ternary DPPC/DOPC/Chol mixtures by introducing a small amount of small proteins (peptides). We use Monte Carlo simulations to explore the mixing phase behavior of the components as a function of the interaction parameter representing the affinity between the proteins and the saturated DPPC chains and for different mixture compositions. At moderate fractions of DPPC, the system is in a two-phase Ld + Lo coexistence, and the proteins exhibit a simple partition behavior between the phases that depends on the protein–lipid affinity parameter. At low DPPC compositions, the mixture is in Ld phase with local nanoscopic ordered domains. The addition of proteins with sufficiently strong attraction to the saturated lipids can induce the separation of a distinct Lo large domain with tightly packed gel-like clusters of proteins and saturated lipids. Consistent with the theory of phase transitions, we observe that the domain sizes grow when the mixture composition is in the vicinity of the critical point. Our simulations show that the addition of a small amount of proteins to such mixtures can cause their size to grow even further and lead to the formation of metastable dynamic Lo domains with sizes comparable to biological rafts.

We investigate the anisotropic frequency-dependent dielectric, THz and IR response of liquid water confined between two planar graphene sheets with force-field- and density-functional-theory-based molecular dynamics simulations. Using spatially resolved anisotropic spectra, we demonstrate the critical role of the volume over which the spectral response is integrated when reporting spatially averaged electric susceptibilities. To analyze the spectra, we introduce a unique decomposition into bulk, interfacial, and confinement contributions, which reveals that confinement effects on the spectra occur only for systems with graphene separation below 1.4 nm, for all frequencies. Based on this decomposition, we discuss the molecular origin of the main absorption features of nanoconfined water from the GHz to the IR regime. We show that, at low frequencies, the 15 GHz Debye peak of interfacial water is redshifted due to a slowdown of collective water reorientations. At high frequencies, the OH stretch at 100 THz blue shifts and a signature of free OH groups emerges, while the HOH bend mode at 50 THz is redshifted. Strikingly, in nanoconfinement, the 20 THz libration band shifts to below 15 THz and broadens drastically, spanning two orders of magnitude in frequency. These results are rationalized by the collective water motion and the structure of the hydrogen-bond network at the water–graphene interface and in two-dimensional water layers, which reveals the intricate behavior of nanoconfined water and its spectral properties.

We apply the methodology of Lustig, with which rigorous expressions for all thermodynamic properties can be derived in any statistical ensemble, to derive expressions for the calculation of thermodynamic properties in the path integral formulation of the quantum-mechanical isobaric–isothermal (NpT) ensemble. With the derived expressions, thermodynamic properties such as the density, speed of sound, or Joule–Thomson coefficient can be calculated in path integral Monte Carlo simulations, fully incorporating quantum effects without uncontrolled approximations within the well-known isomorphism between the quantum-mechanical partition function and a classical system of ring polymers. The derived expressions are verified by simulations of supercritical helium above the vapor–liquid critical point at selected state points using recent highly accurate ab initio potentials for pairwise and nonadditive three-body interactions. We observe excellent agreement of our results with the most accurate experimental data for the density and speed of sound and a reference virial equation of state for helium in the region where the virial equation of state is converged. Moreover, our results agree closer with the experimental data and virial equation of state than the results of semiclassical simulations using the Feynman–Hibbs correction for quantum effects, which demonstrates the necessity to fully include quantum effects by path integral simulations. Our results also show that nonadditive three-body interactions must be accounted for when accurately predicting thermodynamic properties of helium by solely theoretical means.

We explore the effect of Couette flow on knotted linear polymer chains with extensive molecular dynamics simulations. Hydrodynamic interactions are accounted for using multi-particle collision dynamics. The polymer chain, originally containing a simple trefoil knot at rest, is described by a coarse-grained bead-spring model in a coil or globular state. We demonstrate that under shear existing loosely localized knots in polymer coils typically tighten to several segments beyond a certain shear rate threshold. At large shear rates, the polymer undergoes a tumbling-like motion during which knot sizes can fluctuate. In contrast, sheared knotted globules unwind into a convoluted pearl-necklace structure of sub-globules that folds back onto itself and in which knot types change over time.

In this study, we carried out equilibrium molecular dynamics (EMD) simulations of the liquid–liquid (LL) interface between two different Lennard-Jones components with varying miscibility, where we examined the relation between the interfacial tension and the free energy to completely isolate the two liquids using both a mechanical and thermodynamic approach. Using the mechanical approach, we obtained a stress distribution around a quasi-one-dimensional EMD system with a flat LL interface. From the stress distribution, we calculated the LL interfacial tension based on Bakker’s equation, which uses the stress anisotropy around the interface, and measured how it varied with miscibility. The second approach uses thermodynamic integration by enforcing quasi-static isolation of the two liquids to calculate the free energy. This uses the same EMD systems as the mechanical approach, with both extended dry-surface and phantom-wall (PW) schemes applied. When the two components were immiscible, the mechanical interfacial tension and isolation free energy were in good agreement. When the components were miscible, the values were significantly different. From the result of PW for the case of completely mixed liquids, the difference was attributed to the additional free energy required to separate the binary mixture into single components against the osmotic pressure prior to the complete detachment of the two components. This provides a new route to obtain the free energy of mixing.

Determining the stability constant of the complex formed by an organic ligand with a protein is the first stage in the screening of new drugs. Nuclear spin long-lived states, in particular the singlet state, can be used to study the reversible binding of ligands to proteins. In a complex with a protein, the spins of the ligand interact with the spins of the protein, the system of protein and ligand nuclei can relax by a dipole–dipole mechanism, and the lifetime of the singlet state is strongly reduced. In this theoretical study, a system of encounter theory equations with the condition of fast relaxation in free protein was solved to determine the lifetime of the LLS in the presence of protein. It was shown that in the limit of fast chemical exchange, the relaxation of the LLS of the ligand nuclei due to dipole interaction with the protein nuclei is reduced to relaxation by the mechanism of dipole interaction with one proton of the protein, which is located at some effective distance from the ligand nuclei. Numerical calculations were made to test the applicability of the approximations used to process the experimental lifetime dependencies on the ligand concentration and external field, and it was shown that these approximations coincide with the limit of fast exchange in strong and weak magnetic fields, but not in the medium field. An analytical expression for the lifetime of the singlet state of ligand nuclei in an arbitrary magnetic field in the absence of protein was obtained.

The energy-variance-based optimization procedures have proven to be useful tools to describe N-electron spectra. However, the resulting wave functions usually present spin-contaminant contributions. The goal of this work is to reduce the spin contamination of the results arising from the unrestricted doubly occupied configuration interaction method in its energy variance minimization version [Alcoba et al., J. Chem. Phys. 160, 164107 (2024)]. We propose to incorporate the half-projection technique, which allows removing the spin components with even or odd spin quantum number of an approximate N-electron wave function, into the framework of the unrestricted doubly occupied configuration interaction treatment. This implementation can be carried out following several possible ways, whose results are analyzed in detail, in order to show the behavior of each procedure. Numerical determinations performed on selected strongly correlated N-electron systems, in ground and excited states, allow us to assess the most suitable procedure.

Lung cancer is one of the most common cancers in humans. However, there is still a need to understand the underlying mechanisms of a normal cell developing into a cancer cell. Here, we develop the chromosome dynamic structural model and quantify the important characteristics of the chromosome structural ensemble of the normal lung cell and the lung cancer A549 cell. Our results demonstrate the essential relationship among the chromosome ensemble, the epigenetic marks, and the gene expressions, which suggests the linkage between chromosome structure and function. The analysis reveals that the lung cancer cell may have a higher level of relative ensemble fluctuation (micro CFI) and a higher degree of phase separation between the two compartments than the normal lung cell. In addition, the significant conformational “switching off” events (from compartment A to B) are more than the significant conformational “switching on” events during the lung cancerization. We identify “nucleation seeds” or hot spots in chromosomes, which initiate the transitions and determine the mechanisms. The hot spots and interaction network results reveal that the lung cancerization process (from normal lung to A549) and the reversion process have different mechanisms. These investigations have revealed the cell fate determination mechanism of the lung cancer process, which will be helpful for the further prevention and control of cancers.