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The separation of substances into different phases is ubiquitous in nature and important scientifically and technologically. This phenomenon may become drastically different if the species involved, whether molecules or supramolecular assemblies, interconvert. In the presence of an external force large enough to overcome energetic differences between the interconvertible species (forced interconversion), the two alternative species will be present in equal amounts, and the striking phenomenon of steady-state, restricted phase separation into mesoscales is observed. Such microphase separation is one of the simplest examples of dissipative structures in condensed matter. In this work, we investigate the formation of such mesoscale steady-state structures through Monte Carlo and molecular dynamics simulations of three physically distinct microscopic models of binary mixtures that exhibit both equilibrium (natural) interconversion and a nonequilibrium source of forced interconversion. We show that this source can be introduced through an internal imbalance of intermolecular forces or an external flux of energy that promotes molecular interconversion, possible manifestations of which could include the internal nonequilibrium environment of living cells or a flux of photons. The main trends and observations from the simulations are well captured by a nonequilibrium thermodynamic theory of phase transitions affected by interconversion. We show how a nonequilibrium bicontinuous microemulsion or a spatially modulated state may be generated depending on the interplay between diffusion, natural interconversion, and forced interconversion. 

Molecular chirality is a fundamental phenomenon, underlying both life as we know it and industrial pharmaceutical syntheses. Understanding the symmetry breaking phase transitions exhibited by many chiral molecular substances provides basic insights for topics ranging from the origin of life to the rational design of drug manufacturing processes. In this work, we have performed molecular dynamics simulations to investigate the fluid–fluid phase transitions of a flexible three-dimensional four-site chiral molecular model developed by Latinwo et al. [J. Chem. Phys. 145, 154503 (2016)] and Petsev et al. [J. Chem. Phys. 155, 084105 (2021)]. By introducing a bias favoring local homochiral vs heterochiral interactions, the system exhibits a phase transition from a single achiral phase to a single chiral phase that undergoes infrequent interconversion between the two thermodynamically identical chiral states: the L-rich and D-rich phases. According to the phase rule, this reactive binary system has two independent degrees of freedom and exhibits a density-dependent critical locus. Below the liquid–liquid critical locus, there exists a first-order vapor–liquid coexistence region with a single independent degree of freedom. Our results provide basic thermodynamic and kinetic insights for understanding many-body chiral symmetry breaking phenomena. 

The hypothesis that the anomalous behavior of liquid water is related to the existence of a second critical point in deeply supercooled states has long been the subject of intense debate. Recent, sophisticated experiments designed to observe the transformation between the two subcritical liquids on nano- and microsecond time scales, along with demanding numerical simulations based on classical (rigid) models parameterized to reproduce thermodynamic properties of water, have provided support to this hypothesis. A stronger numerical proof requires demonstrating that the critical point, which occurs at temperatures and pressures far from those at which the models were optimized, is robust with respect to model parameterization, specifically with respect to incorporating additional physical effects. Here, we show that a liquid–liquid critical point can be rigorously located also in the WAIL model of water [Pinnick et al., J. Chem. Phys. 137, 014510 (2012)], a model parameterized using ab initio calculations only. The model incorporates two features not present in many previously studied water models: It is both flexible and polarizable, properties which can significantly influence the phase behavior of water. The observation of the critical point in a model in which the water–water interaction is estimated using only quantum ab initio calculations provides strong support to the viewpoint according to which the existence of two distinct liquids is a robust feature in the free energy landscape of supercooled water. 

Much attention has been devoted to water’s metastable phase behavior, including polyamorphism (multiple amorphous solid phases), and the hypothesized liquid-liquid transition and associated critical point. However, the possible relationship between these phenomena remains incompletely understood. Using molecular dynamics simulations of the realistic TIP4P/2005 model, we found a striking signature of the liquid-liquid critical point in the structure of water glasses, manifested as a pronounced increase in long-range density fluctuations at pressures proximate to the critical pressure. By contrast, these signatures were absent in glasses of two model systems that lack a critical point. We also characterized the departure from equilibrium upon vitrification via the non-equilibrium index; water-like systems exhibited a strong pressure dependence in this metric, whereas simple liquids did not. These results reflect a surprising relationship between the metastable equilibrium phenomenon of liquid-liquid criticality and the non-equilibrium structure of glassy water, with implications for our understanding of water phase behavior and glass physics. Our calculations suggest a possible experimental route to probing the existence of the liquid-liquid transition in water and other fluids.

 

ABSTRACT: The dosing of peptide and protein therapeutics is complicated by rapid clearance from the blood pool and poor cellular membrane permeability. Encapsulation into nanocarriers such as liposomes or polymersomes has long been explored to overcome these limitations, but manufacturing challenges have limited clinical translation by these approaches. Recently, inverse Flash NanoPrecipitation (iFNP) has been developed to produce highly loaded polymeric nanocarriers with the peptide or protein contained within a hydrophilic core, stabilized by a hydrophobic polymer shell. Encapsulation of proteins with higher-order structure requires understanding how processing may affect their conformational state. We demonstrate a combined experimental/simulation approach to characterize protein behavior during iFNP processing steps using the Trp-cage protein TC5b as a model. Explicit-solvent fully atomistic molecular dynamics simulations with enhanced sampling techniques are coupled with two-dimensional heteronuclear multiple-quantum coherence nuclear magnetic resonance spectroscopy (2D-HMQC NMR) and circular dichroism to determine the structure of TC5b during mixed-solvent exposure encountered in iFNP processing. The simulations involve atomistic models of mixed solvents and protein to capture the complexity of the hydrogen bonding and hydrophobic interactions between water, dimethylsulfoxide (DMSO), and the protein. The combined analyses reveal structural unfolding of the protein in 11 M DMSO but confirm complete refolding after release from the polymeric nanocarrier back into an aqueous phase. 

Antifreeze proteins (AFPs) are a diverse class of proteins that depress the kinetically observable freezing point of water. AFPs have been of scientific interest for decades, but the lack of an accurate model for predicting AFP activity has hindered the logical design of novel antifreeze systems. To address this, we perform molecular dynamics simulation for a collection of well-studied AFPs. By analyzing both the dynamic behavior of water near the protein surface and the geometric structure of the protein, we introduce a method that automatically detects the ice binding face of AFPs. From these data, we construct a simple neural network that is capable of quantitatively predicting experimentally observed thermal hysteresis from a trio of relevant physical variables. The model’s accuracy is tested against data for 17 known AFPs and 5 non-AFP controls.