Two-dimensional Molecular Dynamics Research Articles

Molecular dynamics in multidimensional space explains how mutations affect the association path of neomycin to a riboswitch

Riboswitches are messenger RNA (mRNA) fragments binding specific small molecules to regulate gene expression. A synthetic N1 riboswitch, inserted into yeast mRNA controls the translation of a reporter gene in response to neomycin. However, its regulatory activity is sensitive to single-point RNA mutations, even those distant from the neomycin binding site. While the association paths of neomycin to N1 and its variants remain unknown, recent fluorescence kinetic experiments indicate a two-step process driven by conformational selection. This raises the question of which step is affected by mutations. To address this, we performed all-atom two-dimensional replica-exchange molecular dynamics simulations for N1 and U14C, U14C[Formula: see text], U15A, and A17G mutants, ensuring extensive conformational sampling of both RNA and neomycin. The obtained neomycin association and binding paths, along with multidimensional free-energy profiles, revealed a two-step binding mechanism, consisting of conformational selection and induced fit. Neomycin binds to a preformed N1 conformation upon identifying a stable upper stem and U-turn motif in the riboswitch hairpin. However, the positioning of neomycin in the binding site occurs at different RNA-neomycin distances for each mutant, which may explain their different regulatory activities. The subsequent induced fit arises from the interactions of the neomycin's N3 amino group with RNA, causing the G9 backbone to rearrange. In the A17G mutant, the critical C6-A17/G17 stacking forms at a closer RNA-neomycin distance compared to N1. These findings together with estimated binding free energies coincide with experiments and elucidate why the A17G mutation decreases and U15A enhances N1 activity in response to neomycin.

Initial Occurrence State and Movability Evaluation of the Gulong Shale Oil Reservoir, Songliao Basin

The Qing-1 layer of the Gulong Depression in the northern Songliao Basin is a liquid-rich shale oil reservoir that has the characteristics of nanopores, high maturity, high gas/oil ratio (GOR), etc. The production performance of wells in the Gulong shale oil reservoir shows the characteristics of “single gas production followed by oil-gas production”. It is difficult to analyze the initial occurrence state and movability of fluid in the shale nanopores using conventional methods. In this study, a comprehensive method, including phase behavior analysis, physical experiments, and molecular simulation, was established to analyze the initial occurrence state and movability of fluid in the Gulong shale oil reservoir. The phase state of the fluid was calculated by the equation of state (EOS), considering nano-confinement effects, and the initial occurrence state was quantitatively evaluated by combining two-dimensional nuclear magnetic resonance (NMR) and molecular dynamics simulation. The movable fluid saturation was quantitatively determined by centrifugal experiments. The results show that the condensate gas state was in small pores, while the volatile oil state was in large pores. The occurrence states of oil were mainly adsorbed oil and free oil. The proportion of adsorbed oil in inorganic pores was about 24.4%, while the proportion of absorbed oil in organic pores was about 57.8%. Based on the cutoff value of T2 before and after the centrifuged laboratory experiments, the movable limit of oil was determined to be 4.5 nm, and the movable fluid saturation was about 11%. The research method proposed in this study has important guiding significance for the initial occurrence state and movability evaluation of similar liquid-rich shale reservoirs.

Screening of Novel Antimicrobial Diastereomers of Azithromycin-Thiosemicarbazone Conjugates: A Combined LC-SPE/Cryo NMR, MS/MS and Molecular Modeling Approach.

A well-known class of antibacterials, 14- and 15-membered macrolides are widely prescribed to treat upper and lower respiratory tract infections. Azithromycin is a 15-membered macrolide antibiotic possessing a broad spectrum of antibacterial potency and favorable pharmacokinetics. Bacterial resistance to marketed antibiotics is growing rapidly and represents one of the major global hazards to human health. Today, there is a high need for discovery of new anti-infective agents to combat resistance. Recently discovered conjugates of azithromycin and thiosemicarbazones, the macrozones, represent one such class that exhibits promising activities against resistant pathogens. In this paper, we employed an approach which combined LC-SPE/cryo NMR, MS/MS and molecular modeling for rapid separation, identification and characterization of bioactive macrozones and their diastereomers. Multitrapping of the chromatographic peaks on SPE cartridges enabled sufficient sample quantities for structure elucidation and biological testing. Furthermore, two-dimensional NOESY NMR data and molecular dynamics simulations revealed stereogenic centers with inversion of chirality. Differences in biological activities among diastereomers were detected. These results should be considered in the process of designing new macrolide compounds with bioactivity. We have shown that this methodology can be used for a fast screening and identification of the macrolide reaction components, including stereoisomers, which can serve as a source of new antibacterials.

History dependent plasticity of glass: A mapping between atomistic and elasto-plastic models

Mesoscale elasto-plastic models, with statistically distributed structural properties and elastic coupling between discrete blocks, have been shown to quantitatively reproduce the main phenomenology observed in the stationary flow state of glasses as modelled at the atomic scale [1]. In the present study, an extension of such approaches is proposed to describe the transient mechanical response of glasses from different off-equilibrium states in the athermal quasi-static limit. Equilibrated liquids are simulated using two-dimensional molecular dynamics, quenched instantaneously to zero temperature, and then sheared. The mechanical observables measured in atomistic and elasto-plastic models are compared at the same length scales to calibrate a state-dependent constitutive law. A physical mechanism is proposed where the structural properties’ evolution rate depends on the magnitude of local plastic deformation events, introducing an effective local memory of previous states in the system. This mechanism naturally leads to a brittle-ductile transition in the mechanical response of glasses, which depends exclusively on the quenched structure. Specifically, initially stable glasses exhibit strain-softening and localization, where the memory of the initial states is lost abruptly after the first plastic rearrangements. On the other hand, systems quenched from high-temperature liquids show a slow strain-hardening with statistically homogeneous plastic deformation. In these initially soft glasses, numerous plastic rearrangements are required to converge toward the stationary flow state. The elasto-plastic model successfully reproduces the stress-strain curves in the transient regime for the whole range of parent temperatures by including this local memory mechanism. The limitations of the model are finally discussed, together with possible improvements.

Rayleigh–Taylor instability in strongly coupled plasma

Rayleigh–Taylor instability (RTI) is the prominent energy mixing mechanism when heavy fluid lies on top of light fluid under the gravity. In this work, the RTI is studied in strongly coupled plasmas using two-dimensional molecular dynamics simulations. The motivation is to understand the evolution of the instability with the increasing correlation (Coulomb coupling) that happens when the average Coulombic potential energy becomes comparable to the average thermal energy. We report the suppression of the RTI due to a decrease in growth rate with increasing coupling strength. The caging effect is expected a physical mechanism for the growth suppression observed in both the exponential and the quadratic growth regimes. We also report that the increase in shielding due to background charges increases the growth rate of the instability. Moreover, the increase in the Atwood number, an entity to quantify the density gradient, shows the enhancement of the growth of the instability. The dispersion relation obtained from the molecular dynamics simulation of strongly coupled plasma shows a slight growth enhancement compared to the hydrodynamic viscous fluid. The RTI and its eventual impact on turbulent mixing can be significant in energy dumping mechanisms in inertial confinement fusion where, during the compressed phases, the coupling strength approaches unity.

NMR and Theoretical Study of In-Pore Diffusivity of Ionic Liquid-Solvent Mixtures.

Despite having a lower energy density than common batteries, electric double-layer capacitors (EDLCs) offer several advantages for high-power applications, including high power density, quick charge and discharge time, and long cycle life. Room-temperature ionic liquids (RTILs) have been intensely studied as promising electrolytes for applications in ELDCs because of their wide potential window, low volatility, as well as thermal and chemical stability. The main deficiency of neat RTILs in such applications is the sluggish diffusivity, which restricts the EDLCs' power density. To alleviate the slow diffusivity, RTILs can be used in a mixture with organic solvents. In this study, we applied two-dimensional exchange nuclear magnetic resonance spectroscopy (2D EXSY NMR) and molecular dynamics (MD) simulations to investigate the diffusivity of anions of an RTIL, namely, 1-butyl-3-methyl-imidazolium bis(trifluoromethylsulfonyl)imide (BMIM+-TFSI-), dissolved in five different organic solvents, in the micropores of activated carbon. We determined that the relative concentrations of ions in solutions in the micropores were higher than those in the bulk solutions and were also solvent-dependent. The ion diffusivities in the pores were found to be almost 2 orders of magnitude slower than in the bulk solutions, with methanol showing the largest relative disparity. These results suggested that the interactions of solvents with the activated carbon are critical not only to the power density of EDLCs but also to the energy density. The comparisons of ion diffusivities between the experiments and the MD simulations suggest the need to consider also the surface functionalities of activated carbon for the simulation of ion diffusion in the micropores of activated carbon.

Electrochemical atomic force microscopy of two-dimensional trinuclear ruthenium clusters molecular assembly and dynamics under redox state control.

Mixed-valence ruthenium trinuclear clusters containing dichloroacetates were synthesized, and the self-assembly of a single molecular adlayer composed of these clusters on a graphite surface was investigated by atomic force microscopy (AFM). AFM clearly revealed the dynamics of two-dimensional (2D) structure formation as well as the molecular characteristics of the adlayers at different electrochemical interfaces. The results verified that the design of metal complexes is important not only for redox chemistry but also for molecular assembly and nanoarchitecture construction.

What Is Being Measured with P-Bearing NMR Probe Molecules Adsorbed on Zeolites?

Elucidating the nature, strength, and siting of acid sites in zeolites is fundamental to fathom their reactivity and catalytic behavior. Despite decades of research, this endeavor remains a major challenge. Trimethylphosphine oxide (TMPO) has been proposed as a reliable probe molecule to study the acid properties of solid acid catalysts, allowing the identification of distinct Brønsted and Lewis acid sites and the assessment of Brønsted acid strengths. Recently, doubts have been raised regarding the assignment of the 31P NMR resonances of TMPO-loaded zeolites. Here, it is shown that a judicious control of TMPO loading combined with two-dimensional 1H-31P HETCOR solid-state NMR, DFT, and ab initio molecular dynamics (AIMD)-based computational modeling provides an unprecedented atomistic description of the host-guest and guest-guest interactions of TMPO molecules confined within HZSM-5 molecular-sized voids. 31P NMR resonances usually assigned to TMPO molecules interacting with Brønsted sites of different acid strength arise instead from both changes in the probe molecule confinement effects at ZSM-5 channel system and the formation of protonated TMPO dimers. Moreover, DFT/AIMD shows that the 1H and 31P NMR chemical shifts strongly depend on the siting of the framework aluminum atoms. This work overhauls the current interpretation of NMR spectra, raising important concerns about the widely accepted use of probe molecules for studying acid sites in zeolites.

Atomistic simulation of creep deformation mechanisms in nickel-based single crystal superalloys

Abstract In this paper, the creep deformation mechanisms are investigated in nickel-based single crystal superalloys. Two-dimensional molecular dynamics (MD) simulations are conducted to model various temperatures, stress conditions, and phase interface crystal orientations. Ni-based single-crystal superalloys are of great importance in the aircraft industry due to their excellent high temperature creep resistance. This characteristic mainly originates from two features considered in their structure; firstly, their two-phase micro-structure comprising gamma γ and gamma prime γ ′ , and secondly the nature of this superalloy itself, which is a single-crystal. MD is a powerful tool to gain insight into creep behavior at small scales, where dislocations and high-temperature diffusional phenomena are the most critical deformation agents. The parameters considered in the creep deformation are temperature, stress, and phase interface crystal orientation. The simulations are observed in various temperature conditions including 1100, 1200, 1400, 1600, and 1700 K. Stress levels are applied from 0.5 to 5.0 GPa with a sequence of 0.5 GPa, and phase interface crystal orientations are imposed on (001), (011) and (111). Various mechanisms are detected, including the γ ′ precipitate shearing, micro-twinning, the diffusion-mediated climb that allows the dislocations to bypass the γ ′ precipitates, and rafting that refers to directional γ ′ coarsening. The results are shown to be in good agreement with available experimental data. The steady-state creep phase is associated with a constant strain rate, which is calculated for each model. The power-law equation is employed to predict the steady-state strain rate as a function of stress, temperature, the required activation energy, and the stress exponent parameter. Finally, a deformation map is presented for different phase interface models based on the stress exponent parameter values.

Cyclodextrin complexation studies as the first step for repurposing of chlorpromazine.

The antipsychotic drug chlorpromazine (CPZ) has potential for the treatment of acute myeloid leukemia, if central nervous system side-effects resulting from its passage through the blood-brain barrier can be prevented. A robust drug delivery system for repurposed CPZ would be drug-in-cyclodextrin-in-liposome that would redirect the drug away from the brain while avoiding premature release in the circulation. As a first step, CPZ complexation with cyclodextrin (CD) has been studied. The stoichiometry, binding constant, enthalpy, and entropy of complex formation between CPZ and a panel of CDs was investigated by isothermal titration calorimetry (ITC). All the tested CDs were able to include CPZ, in the form of 1:1, 1:2 or a mixture of 1:1 and 1:2 complexes. In particular, a substituted γ-CD, sugammadex (the octasodium salt of octakis(6-deoxy-6-S-(2-carboxyethyl)-6-thio)cyclomaltooctaose), formed exclusively 1:2 complexes with an extremely high association constant of 6.37×109 M-2. Complexes were further characterized by heat capacity changes, one- and two-dimensional (ROESY) nuclear magnetic resonance(NMR) spectroscopy and molecular dynamics simulations. Finally, protection of CPZ against photodegradation by CDs was assessed. This was accelerated rather than reduced by complexation with CD. Altogether these results provide a molecular basis for the use of CD in delayed release formulations for CPZ.

The emergence of inertial waves from coherent vortex source in strongly coupled dusty plasma

The evolution of isotropic, nondispersive, inertial waves emerging from an unsteady initial coherent vortex source is studied for strongly correlated dusty plasma using two-dimensional molecular dynamics simulation. In this study, the effects of azimuthal speed of a vortex source, strong correlation, large screening, and the compressibility of the medium on the propagation of generated inertial waves have been presented. It has been observed that these inertial waves only exist when the angular speed or azimuthal speed of the vortex source (U0) is larger than the transverse sound speed (Ct) of the system. The estimated speed of the nonlinear wave (CNLW) is found to be always larger and close to longitudinal sound speed (Cl) of the system for the range of coupling and screening parameters studied. We find that spontaneously generated inertial wave speed in dusty plasma is suppressed by the compressibility and dust-neutral drag of the system and is less sensitive to coupling strength. We also report a transition from “incompressible to compressible” flow. This transition is found to depend on the screening parameter and azimuthal speed of the vortex source. The existence of a critical Mach number Mc≈0.35 is found (where Mc=U0/Cl), above which inertial waves are found to exist, indicating the compressible nature of the wave.

Phonon confinement and transport in ultrathin films

Thermal transport by phonons in films with thicknesses of less than 10 nm is investigated in a soft system (Lennard-Jones argon) and a stiff system (Tersoff silicon) using two-dimensional lattice dynamics calculations and the Boltzmann transport equation. This approach uses a unit cell that spans the film thickness, which removes approximations related to the finite cross-plane dimension required in typical three-dimensional-based approaches. Molecular dynamics simulations are performed to obtain finite-temperature structures for the lattice dynamics calculations and to predict thermal conductivity benchmarks. Thermal conductivity decreases with decreasing film thickness until the thickness reaches four unit cells (2.1 nm) for argon and three unit cells (1.6 nm) for silicon. With a further decrease in film thickness, thermal conductivity plateaus in argon while it increases in silicon. This unexpected behavior, which we identify as a signature of phonon confinement, is a result of an increased contribution from low-frequency phonons, whose density of states increases as the film thickness decreases. Phonon mode-level analysis suggests that confinement effects emerge below thicknesses of ten unit cells (5.3 nm) for argon and six unit cells (3.2 nm) for silicon. Thermal conductivity predictions based on the bulk phonon properties combined with a boundary scattering model do not capture the low thickness behavior. To match the two-dimensional lattice dynamics and molecular dynamics predictions for larger thicknesses, the three-dimensional lattice dynamics calculations require a finite specularity parameter that in some cases approaches unity. These findings point to the challenges associated with interpreting experimental thermal conductivity measurements of ultrathin silicon films, where surface roughness and a native oxide layer impact phonon transport.

A two-dimensional replica-exchange molecular dynamics method for simulating RNA folding using sparse experimental restraints.

We present a 2D replica exchange protocol incorporating secondary structure information to dramatically improve 3D RNA folding using molecular dynamics simulations. We show that incorporating base-pairing restraints into all-atom, explicit solvent simulations enables the accurate recapitulation of the global tertiary fold for 4 representative RNAs ranging in length from 24 to 68 nt. This method can potentially utilize base-pairing information from a wide variety of experimental inputs to predict complex RNA tertiary folds including pseudoknots, multi-loop junctions, and non-canonical interactions.

Role of Solid Wall Properties in the Interface Slip of Liquid in Nanochannels.

A two-dimensional molecular dynamics model of the liquid flow inside rough nanochannels is developed to investigate the effect of a solid wall on the interface slip of liquid in nanochannels with a surface roughness constructed by rectangular protrusions. The liquid structure, velocity profile, and confined scale on the boundary slip in a rough nanochannel are investigated, and the comparison of those with a smooth nanochannel are presented. The influence of solid wall properties, including the solid wall density, wall-fluid coupling strength, roughness height and spacing, on the interfacial velocity slip are all analyzed and discussed. It is indicated that the rough surface induces a smaller magnitude of the density oscillations and extra energy losses compared with the smooth solid surface, which reduce the interfacial slip of liquid in a nanochannel. In addition, once the roughness spacing is very small, the near-surface liquid flow dominates the momentum transfer at the interface between liquid and solid wall, causing the role of both the corrugation of wall potential and wall-fluid coupling strength to be less obvious. In particular, the slip length increases with increasing confined scales and shows no dependence on the confined scale once the confined scale reaches a critical value. The critical confined scale for the rough channel is larger than that of the smooth scale.

A Local Region Molecular Dynamics Simulation Method for Nanoscale Sliding Contacts

Computational efficiency and accuracy always conflict with each other in molecular dynamics (MD) simulations. How to enhance the computational efficiency and keep accuracy at the same time is concerned by each corresponding researcher. However, most of the current studies focus on MD algorithms, and if the scale of MD model could be reduced, the algorithms would be more meaningful. A local region molecular dynamics (LRMD) simulation method which can meet these two factors concurrently in nanoscale sliding contacts is developed in this paper. Full MD simulation is used to simulate indentation process before sliding. A criterion called contribution of displacement is presented, which is used to determine the effective local region in the MD model after indentation. By using the local region, nanoscale sliding contact between a rigid cylindrical tip and an elastic substrate is investigated. Two two-dimensional MD models are presented, and the friction forces from LRMD simulations agree well with that from full MD simulations, which testifies the effectiveness of the LRMD simulation method for two-dimensional cases. A three-dimensional MD model for sliding contacts is developed then to show the validity of the LRMD simulation method further. Finally, a discussion is carried out by the principles of tribology. In the discussion, two two-dimensional full MD models are used to simulate the nanoscale sliding contact problems. The results indicate that original smaller model will induce higher equivalent scratching depth, and then results in higher friction forces, which will help to explain the mechanism how the LRMD simulation method works. This method can be used to reduce the scale of MD model in large scale simulations, and it will enhance the computational efficiency without losing accuracy during the simulation of nanoscale sliding contacts.

Analysis of velocity slipping at wall boundary under rarefied gas condition based on the effect of viscosity

PurposeVelocity slipping model, based on the stratification theory (the film in inflatable support area of aerostatic guide way was divided into near wall layer, thin layer and continuous flow layer in the direction of height), was established, and the model was combined with viscosity changes in each layer.Design/methodology/approachSimulated and analyzed by LAMMPS and two-dimensional molecular dynamics method, some relevant conclusions were drawn.FindingsAt a high temperature, viscosity is low, velocity slipping is large and velocity gaps in near-wall layer and thin layer are large. When the temperature is constant, the dimensionless slipping length and Kn number are linear.Research limitations/implicationsThe effect of the equivalent viscosity on gas slipping model is proposed. viscosity is smaller, gas velocity slipping is greater, temperature is higher, gas velocity slipping is greater, velocity gap of near wall layer and thin layer is larger. When the temperature is constant, the dimensionless slipping length ls and Kn number are linear.Originality/valueThe global model of lubricating film velocity slipping between plates was established, and mathematical expression of slipping model in each layer, based on the stratification theory, was presented.

Modeling Carbon Dioxide Vibrational Frequencies in Ionic Liquids: III. Dynamics and Spectroscopy.

In recent years, interest in carbon capture and sequestration has led to numerous investigations of the ability of ionic liquids to act as recyclable CO2-sorbent materials. Herein, we investigate the structure and dynamics of a model physisorbing ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate ([C4C1Im][PF6]), from the perspective of CO2 using two-dimensional (2D) IR spectroscopy and molecular dynamics simulations. A direct comparison of experimentally measured and calculated 2D IR line shapes confirms the validity of the simulations and spectroscopic calculations. Taken together, the simulations and experiments reveal new insights into the interactions of a CO2 solute with the surrounding ionic liquid and how these interactions manifest in the 2D IR spectra. In particular, higher CO2 asymmetric stretch vibrational frequencies are associated with softer, less populated solvent cages and lower frequencies are associated with tighter, more highly populated solvent cages. The CO2 interacts most strongly with the anions, and these interactions persist for more than 1 ns. The second strongest interactions are with the imidazolium cation ring that last 100 ps, and the weakest interactions are with the cation butyl tail that persist for 10 ps. The principal contributors to spectral diffusion of the CO2 asymmetric stretch vibrational frequency due to the dynamical evolution of the solvent are through Lennard-Jones interactions at short times and electrostatics at long times.

Simulations of submonolayer Xe on Pt(111): The case for a chaotic low temperature phase.

Molecular dynamics simulations are reported for the structural and thermodynamic properties of submonolayer xenon adsorbed on the (111) surface of platinum for temperatures up to the (apparently incipient) triple point and beyond. While the motion of the atoms in the surface plane is treated with a standard two-dimensional molecular dynamics simulation, the model takes into consideration the thermal excitation of quantum states associated with surface-normal dynamics in an attempt to describe the apparent smoothing of the corrugation with increasing temperature. We examine the importance of this thermal smoothing to the relative stability of several observed and proposed low-temperature structures. Structure factor calculations are compared to experimental results in an attempt to determine the low temperature structure of this system. These calculations provide strong evidence that, at very low temperatures, the domain wall structure of a xenon monolayer adsorbed on a Pt(111) substrate possesses a chaotic-like nature, exhibiting long-lived meta-stable states with pinned domain walls, these walls having narrow widths and irregular shapes. This result is contrary to the standard wisdom regarding this system, namely, that the very low temperature phase of this system is a striped incommensurate phase. We present the case for further experimental investigation of this and similar systems as possible examples of chaotic low temperature phases in two dimensions.

Interplay of single particle and collective response in molecular dynamics simulation of dusty plasma system

The collective response of the plasma medium is well known and has been explored extensively in the context of dusty plasma medium. On the other hand, the individual particle response associated with the collisional character giving rise to the dissipative phenomena has not been explored adequately. In this paper, two-dimensional molecular dynamics simulation of dust particles interacting via Yukawa potential has been considered. It has been shown that disturbances induced in a dust crystal elicit both collective and single particle responses. Generation of a few particles moving at speeds considerably higher than acoustic and/or shock speed (excited by the external disturbance) is observed. This is an indication of a single particle response. Furthermore, as these individual energetic particles propagate, the dust crystal is observed to crack along their path. Initially when the energy is high, these particles generate secondary energetic particles by the collisional scattering process. However, ultimately as these particles slow down they excite a collective response in the dust medium at secondary locations in a region which is undisturbed by the primary external disturbance. The condition when the cracking of the crystal stops and collective excitations get initiated has been identified quantitatively. The trailing collective primary disturbances would thus often encounter a disturbed medium with secondary and tertiary collective perturbations, thereby suffering significant modification in its propagation. It is thus clear that there is an interesting interplay (other than mere dissipation) between the single particle and collective response which governs the dynamics of any disturbance introduced in the medium.

Development of isothermal-isobaric replica-permutation method for molecular dynamics and Monte Carlo simulations and its application to reveal temperature and pressure dependence of folded, misfolded, and unfolded states of chignolin.

We developed a two-dimensional replica-permutation molecular dynamics method in the isothermal-isobaric ensemble. The replica-permutation method is a better alternative to the replica-exchange method. It was originally developed in the canonical ensemble. This method employs the Suwa-Todo algorithm, instead of the Metropolis algorithm, to perform permutations of temperatures and pressures among more than two replicas so that the rejection ratio can be minimized. We showed that the isothermal-isobaric replica-permutation method performs better sampling efficiency than the isothermal-isobaric replica-exchange method and infinite swapping method. We applied this method to a β-hairpin mini protein, chignolin. In this simulation, we observed not only the folded state but also the misfolded state. We calculated the temperature and pressure dependence of the fractions on the folded, misfolded, and unfolded states. Differences in partial molar enthalpy, internal energy, entropy, partial molar volume, and heat capacity were also determined and agreed well with experimental data. We observed a new phenomenon that misfolded chignolin becomes more stable under high-pressure conditions. We also revealed this mechanism of the stability as follows: TYR2 and TRP9 side chains cover the hydrogen bonds that form a β-hairpin structure. The hydrogen bonds are protected from the water molecules that approach the protein as the pressure increases.