The 50 most-cited articles in The Journal of Physical Chemistry B, 2021

Polymeric materials play critical role in many current technologies. Among them, adaptive polymeric materials with dynamic (reversible) bonds exhibit unique properties and provide exciting opportunities for various future technologies. Dynamic bonds enable structural rearrangements in polymer networks in specific conditions. Replacement of a few covalent bonds by dynamic bonds can enhance polymeric properties, e.g., strongly improve the toughness and the adhesive properties of polymers. Moreover, they provide recyclability and enable new properties, such as self-healing and shape memory effects. We briefly overview new developments in the field of polymers with dynamic bonds and current understanding of their dynamic properties. We further highlight several examples of unique properties of polymers with dynamic bonds and provide our perspectives for them to be used in many current and future applications.

An accurate model for macroscale disordered assemblies of biological macromolecules such as those formed in so-called membraneless organelles would greatly assist in studying their structure, function, and dynamics. Recent evidence has suggested that liquid-liquid phase separation (LLPS) underlies the formation of membraneless organelles. While the general mechanism of exchange of macromolecule/water for macromolecule/macromolecule interactions is known to be the driving force for LLPS, the specific interactions involved are not well understood. One way that protein-water and protein-protein interactions have been understood historically is via hydrophobicity scales. However, these scales are typically optimized for describing these relative interactions in certain cases, such as protein folding or insertion of proteins into membranes. To better describe the relative interactions of proteins that undergo LLPS, we have developed a new, data-driven hydrophobicity scale. To determine the new scale, we used coarse-grained molecular dynamics simulations using the hydrophobicity scale…

The concept of water-in-salt electrolytes was introduced recently, and these systems have been successfully applied to yield extended operation voltage and hence significantly improved energy density in aqueous Li-ion batteries. In the present work, results of X-ray scattering and Fourier-transform infrared spectra measurements over a wide range of temperatures and salt concentrations are reported for the LiTFSI (lithium bis(trifluoromethane sulfonyl)imide)-based water-in-salt electrolyte. Classical molecular dynamics simulations are validated against the experiments and used to gain additional information about the electrolyte structure. Based on our analyses, a new model for the liquid structure is proposed. Specifically, we demonstrate that at the highest LiTFSI concentration of 20 m the water network is disrupted, and the majority of water molecules exist in the form of isolated monomers, clusters, or small aggregates with chain-like configurations. On the other hand, TFSI – anions are connected to each other and form a network. This description is fundamentally different from…

QM/MM simulations have become an indispensable tool in many chemical and biochemical investigations. Considering the tremendous degree of success, including recognition by a 2013 Nobel Prize in Chemistry, are there still "burning challenges" in QM/MM methods, especially for biomolecular systems? In this short Perspective, we discuss several issues that we believe greatly impact the robustness and quantitative applicability of QM/MM simulations to many, if not all, biomolecules. We highlight these issues with observations and relevant advances from recent studies in our group and others in the field. Despite such limited scope, we hope the discussions are of general interest and will stimulate additional developments that help push the field forward in meaningful directions.

Proteins are the molecular machines of life. The multitude of possible conformations that proteins can adopt determines their free-energy landscapes. However, the inherently high dimensionality of a protein free-energy landscape poses a challenge to deciphering how proteins perform their functions. For this reason, dimensionality reduction is an active field of research for molecular biologists. The uniform manifold approximation and projection (UMAP) is a dimensionality reduction method based on a fuzzy topological analysis of data. In the present study, the performance of UMAP is compared with that of other popular dimensionality reduction methods such as t-distributed stochastic neighbor embedding (t-SNE), principal component analysis (PCA), and time-structure independent components analysis (tICA) in the context of analyzing molecular dynamics simulations of the circadian clock protein VIVID. A good dimensionality reduction method should accurately represent the data structure on the projected components. The comparison of the raw high-dimensional data with the projections…

Preserving the correct dynamics at the coarse-grained (CG) level is a pressing problem in the development of systematic CG models in soft matter simulation. Starting from the seminal idea of simple time-scale mapping, there have been many efforts over the years toward establishing a meticulous connection between the CG and fine-grained (FG) dynamics based on fundamental statistical mechanics approaches. One of the most successful attempts in this context has been the development of CG models based on the Mori-Zwanzig (MZ) theory, where the resulting equation of motion has the form of a generalized Langevin equation (GLE) and closely preserves the underlying FG dynamics. In this Review, we describe some of the recent studies in this regard. We focus on the construction and simulation of dynamically consistent systematic CG models based on the GLE, both in the simple Markovian limit and the non-Markovian case. Some recent studies of physical effects of memory are also discussed. The Review is aimed at summarizing recent developments in the field while highlighting the major challenges…

Liquid-liquid phase separation (LLPS) of proteins has recently been associated with the onset of numerous diseases. Despite several studies in this area of protein aggregation, buffer-specific effects always seem to be overlooked. In this study we investigated the influence of buffers on the phase stability of hen egg-white lysozyme (HEWL) and its respective protein-protein interactions by measuring the cloud point temperature, second virial coefficient, and interaction diffusion coefficient of several HEWL-buffer solutions (MOPS, phosphate, HEPES, cacodylate) at pH 7.0. The results indicate that the buffer molecules, depending on their hydration, adsorb on the protein surface, and modulate their electrostatic stability. The obtained information was used to extend the recently developed coarse-grained protein model to incorporate buffer-specific effects. Treated by Wertheim's perturbation theory the model qualitatively correctly predicted the experimentally observed phase separation of all investigated HEWL-buffer solutions, and further allowed us to predict the phase stability of…

Disordered proteins frequently serve as interaction hubs involving a constrained variety of partners. Complexes with different partners frequently exhibit distinct binding modes, involving regions that remain disordered in the bound state. While the conformational properties of disordered proteins are well-characterized in their free states, less is known about the molecular mechanisms by which specificity can be achieved not with one but with multiple partners. Using the energy landscape theory concept of protein frustration, we demonstrate that complexes of disordered proteins exhibit a high degree of local frustration, especically at the binding interface. These suboptimal interactions lead to the possibility of multiple bound substates, each displaying distinct frustration patterns, which are differently populated in complexes with different partners. These results explain how specificity of disordered proteins can be achieved without a single common bound conformation and how the confliict between different interactions can be used to control the binding to multiple partners.

This perspective article highlights recent progress and emerging challenges in understanding the formation and function of membraneless organelles (MLOs). A long-term goal in the MLO field is to identify the sequence-encoded rules that dictate the formation of compositionally controlled biomolecular condensates, which cells utilize to perform a wide variety of functions. The molecular organization of the different components within a condensate can vary significantly, ranging from a homogeneous mixture to core-shell droplet structures. We provide many examples to highlight the richness of the observed behavior and potential research directions for improving our mechanistic understanding. The tunable environment within condensates can, in principle, alter enzymatic activity significantly. We examine recent examples where this was demonstrated, including applications in synthetic biology. An important question about MLOs is the role of liquid-like material properties in biological function. We discuss the need for improved quantitative characterization tools and the development of…

Electrochemical sensors have emerged as important diagnostic tools in recent years, due to their simplicity and ease of use. Compared to instrumental analysis methods that use complicated experimental and data analysis techniques─such as mass spectrometry, nuclear magnetic resonance (NMR), spectrophotometric methods, and chromatography─electrochemical sensors show promise for use in a wide range of real-time and in situ applications such as pharmaceutical testing, environmental monitoring, and medical diagnostics. In order to identify analytes in complex and/or biological samples, materials used for both the electrode materials and the chemically selective layer have been evolving throughout the years for optimizing the analytical performance of electrochemical sensors to increase sensitivity, selectivity and linear range. In this Perspective, attention will be focused on different types of materials that have been used for electrochemical sensing, including new combinations of well-studied materials as well as novel strategies to enhance the performance of sensing devices. The…

data obtained from SCAN0 DFT calculations. For the electronic properties of water, a separate deep neural network potential is trained by using the Deep Wannier method based on the maximally localized Wannier functions of the equilibrated trajectory at the SCAN0 level. The structural, dynamic, and electric properties of water were analyzed. The hydrogen-bond structures, density, infrared spectra, diffusion coefficients, and dielectric constants of water, in the electronic ground state, are computed by using a large simulation box and long simulation time. For the properties involving electronic excitations, we apply the GW approximation within many-body perturbation theory to calculate the quasiparticle density of states and bandgap of water. Compared to the SCAN functional, mixing exact exchange mitigates the self-interaction error in the meta-generalized-gradient approximation and further softens liquid water toward the experimental direction. For most of the water properties, the SCAN0 functional shows a systematic improvement over the SCAN functional. However, some important…

Coacervates are a type of liquid-liquid phase separated (LLPS) droplets that can serve as models of membraneless organelles (MLOs) in living cells. Peptide-nucleotide coacervates have been widely used to mimic properties of ribonucleoprotein (RNP) granules, but the thermal stability and the role of base stacking is still poorly understood. Here, we report a systematic investigation of coacervates formed by five different nucleoside triphosphates (NTPs) with poly-l-lysine and poly-l-arginine as a function of temperature. All studied combinations exhibit an upper critical solution temperature (UCST), and a temperature-dependent critical salt concentration, originating from a significant nonelectrostatic contribution to the mixing free energy. Both the enthalpic and entropic parts of this nonelectrostatic interaction decrease in the order G/A/U/C/T, in accordance with nucleobase stacking free energies. Partitioning of two dyes proves that the local hydrophobicity inside the peptide-nucleotide coacervates is different for every nucleoside triphosphate. We derive a simple relation…

The phase separation of biomolecules has become the focus of intense research in the past decade, with a growing body of research implicating this phenomenon in essentially all biological functions, including but not limited to homeostasis, stress responses, gene regulation, cell differentiation, and disease. Excellent reviews have been published previously on the underlying physical basis of liquid–liquid phase separation (LLPS) of biological molecules ( Nat. Phys. 2015, 11, 899–904) and LLPS as it occurs natively in physiology and disease ( Science 2017, 357, eaaf4382; Biochemistry 2018, 57, 2479–2487; Chem. Rev. 2014, 114, 6844–6879). Here, we review how the theoretical physical basis of LLPS has been used to better understand the behavior of biomolecules that undergo LLPS in natural systems and how this understanding has also led to the development of novel synthetic systems that exhibit biomolecular phase separation, and technologies that exploit these phenomena. In part 1 of this Review, we explore the theory behind the phase separation of biomolecules and synthetic…

The past two decades witnessed the development of a new type of solvent system, named deep eutectic solvents, which have become increasingly investigated because they offer new and potentially favorable properties, such as wide tunability in electrochemical, mechanical, and transport properties. Deep eutectic solvent (DES) systems are composed of at least one main solvent and an additional component that is meant to interrupt the original solvent/solvent interactions, thereby introducing lower melting points relative to each individual component. Ethaline (a 1:2 mol % mixture of choline chloride and ethylene glycol) is one of the most promising DES systems. However, it is also known to be very hygroscopic, which is a constant concern because water absorption during the use of ethaline alters its properties. Within this work, we demonstrate that modest amounts of water addition (1-10%) to ethaline are of little concern for practical use and can even lead to performance improvements, such as accelerated relaxation and solvation. In contrast, very small amounts of <1% of water lead to…

The transport properties of water-in-salt lithium bis(trifluoromethane sulfonyl)imide (LiTFSI) aqueous electrolytes were studied using classical molecular dynamics (MD) simulations. At high salt concentrations of 20 m, the calculated viscosity, self-diffusion coefficients, ionic conductivity, the inverse Haven ratio, and the Li + apparent transference number all agree with previous experimental results quantitatively. Furthermore, analyses show that the high apparent transference number for Li + is due to the fact that the dynamics of TFSI – decrease more quickly with increasing salt concentration than the dynamics of Li + ions due to the formation of a TFSI – network. In addition, it was shown that the conduction of Li + ions through the highly concentrated electrolyte occurs mainly via a hopping mechanism instead of a vehicular mechanism hypothesized in earlier studies of this system.

ABSTRACT Free energies of hydration are of fundamental interest for modeling and understanding conformational and phase equilibria of macromolecular solutes in aqueous phases. Of particular relevance to systems such as intrinsically disordered proteins are the free energies of hydration and hydration structures of model compounds that mimic charged sidechains of Arg, Lys, Asp, and Glu. Here, we deploy a Thermodynamic Cycle based Proton Dissociation (TCPD) approach in conjunction with data from direct measurements to obtain estimates for the free energies of hydration for model compounds that mimic the sidechains of Arg + , Lys + , Asp - , and Glu - . Irrespective of the choice made for the hydration free energy of the proton, the TCPD approach reveals clear trends regarding the free energies of hydration for Arg + , Lys + , Asp - , and Glu - . These trends include asymmetries between the hydration free energies of acidic (Asp - and Glu - ) and basic (Arg + and Lys + ) residues. Further, the TCPD analysis, which relies on a combination of experimental data, shows that the free energy…

High Resolution Image Download MS PowerPoint Slide The poor performance of many existing nonpolarizable ion force fields is typically blamed on either the lack of explicit polarizability, the absence of charge transfer, or the use of unreduced Coulomb interactions. However, this analysis disregards the large and mostly unexplored parameter range offered by the Lennard-Jones potential. We use a global optimization procedure to develop water-model-transferable force fields for the ions K +, Na +, Cl –, and Br – in the complete parameter space of all Lennard-Jones interactions using standard mixing rules. No extra-thermodynamic assumption is necessary for the simultaneous optimization of the four ion pairs. After an optimization with respect to the experimental solvation free energy and activity, the force fields reproduce the concentration-dependent density, ionic conductivity, and dielectric constant with high accuracy. The force field is fully transferable between simple point charge/extended and transferable intermolecular potential water models. Our results show that a…

Intrinsically disordered proteins play a crucial role in cellular phase separation, yet the diverse molecular forces driving phase separation are not fully understood. It is of utmost importance to understand how peptide sequence, and particularly the balance between the peptides' short- and long-range interactions with other peptides, may affect the stability, structure, and dynamics of liquid-liquid phase separation in protein condensates. Here, using coarse-grained molecular dynamics simulations, we studied the liquid properties of the condensate in a series of polymers in which the ratio of short-range dispersion interactions to long-range electrostatic interactions varied. As the fraction of mutations that participate in short-range interactions increases at the expense of long-range electrostatic interactions, a significant decrease in the critical temperature of phase separation is observed. Nevertheless, sequences with a high fraction of short-range interactions exhibit stabilization, which suggests compensation for the loss of long-range electrostatic interactions.…

Polyelectrolyte complex micelles (PCMs) are a unique class of self-assembled nanoparticles that form with a core of associated polycations and polyanions, microphase-separated from neutral, hydrophilic coronas in aqueous solution. The hydrated nature and structural and chemical versatility make PCMs an attractive system for delivery and for fundamental polymer physics research. By leveraging block copolymer design with controlled self-assembly, fundamental structure-property relationships can be established to tune the size, morphology, and stability of PCMs precisely in pursuit of tailored nanocarriers, ultimately offering storage, protection, transport, and delivery of active ingredients. This perspective highlights recent advances in predictive PCM design, focusing on (i) structure-property relationships to target specific nanoscale dimensions and shapes and (ii) characterization of PCM dynamics primarily using time-resolved scattering techniques. We present several vignettes from these two emerging areas of PCM research and discuss key opportunities for PCM design to advance…

Recently, thermoset vitrimer polymers have shown significant promise for structural applications because of their ability to be reshaped and remolded due to their covalent adaptive network (CAN). In these vitrimers, the transesterification reaction is responsible for the CAN, where the efficiency of the reaction is controlled either by organic or by organometallic catalysts. Understanding the mechanism of the transesterification reaction in the bulk phase using direct experimental techniques is extremely difficult due to the highly cross-linked complex structure of thermosetting vitrimers. Therefore, we use solution-phase experiments to investigate the catalytic efficiency and to guide density functional theory (DFT) simulations of the transesterification reaction mechanism with catalysts triazabicyclodecene (TBD), zinc acetate (Zn(OAc) 2 ), 1-methylimidazole (1-MI), and dibutyltin oxide (DBTO). The estimated catalytic efficiency from the detailed DFT reaction path calculations follows the order TBD ≳ DBTO ≳ Zn(OAc) 2 > 1-MI, which agrees with the experimental results. In addition…

Ionic surfactants are known to build up higher interfacial pressures at oil/water interfaces than at air/water interfaces for the same surfactant bulk concentration. Here, we systematically investigate this effect through atomistic molecular dynamics (MD) simulations of surfactant-loaded air/water and oil/water interfaces. Two prototypical ionic surfactants, C 12 TAB and sodium dodecyl sulfate (SDS), are studied and found to give consistent results, which are also robust with respect to variations in the simulation force field. The simulations reproduce the experimental interfacial pressure data on a semiquantitative level and reveal that the influence of oil on the surfactants’ in-plane distribution is a major contribution to the observed effect, albeit insufficient to be the sole reason. The simulations are further analyzed with regard to surfactant/oil cooperative/competitive effects that have been invoked recently as an explanation. However, the interfacial orientation of oil molecules, a presumable indicator for such behavior, is found to display changes only for high levels of…

High Resolution Image Download MS PowerPoint Slide In this work, we resolve a long-standing issue concerning the local structure of molten MgCl 2 by employing a multimodal approach, including X-ray scattering and Raman spectroscopy, along with the theoretical modeling of the experimental spectra based on ab initio molecular dynamics (AIMD) simulations utilizing several density functional theory (DFT) methods. We demonstrate the reliability of AIMD simulations in achieving excellent agreement between the experimental and simulated spectra for MgCl 2 and 50 mol % MgCl 2 + 50 mol % KCl, and ZnCl 2, thus allowing structural insights not directly available from experiment alone. A thorough computational analysis using five DFT methods provides a convergent view that octahedrally coordinated magnesium in pure MgCl 2 upon melting preferentially coordinates with five chloride anions to form distorted square pyramidal polyhedra that are connected via corners and to a lesser degree via edges. This is contrasted with the results for ZnCl 2, which does not change its tetrahedral coordination on…

High Resolution Image Download MS PowerPoint Slide Thermally activated delayed fluorescence (TADF) has recently become an extensively investigated phenomenon due to its high potential for application in organic optoelectronics. Currently, there is still lack of a model describing correctly basic photophysical parameters of organic TADF emitters. This article presents such a photophysical model describing the rates of intersystem crossing (ISC), reverse ISC (rISC), and radiative deactivation in various media and emphasizing key importance of molecular vibrations on the example of a popular TADF dye 9,10-dihydro-9,9-dimethyl-10-(4-(4,6-diphenyl-1,3,5-triazin-2-yl)phenyl)-acridine (DMAC-TRZ). The presented experimental and theoretical investigations prove that ISC and rISC can occur efficiently between the singlet and triplet states of the same charge-transfer nature ( 1 CT and 3 CT, respectively). In emitters with the orthogonal donor and acceptor fragments, such spin-forbidden 1 CT ↔ 3 CT transitions are activated by molecular vibrations. Namely, the change of dihedral angle between…

The COVID-19 pandemic has emerged as a global medico-socio-economic disaster. Given the lack of effective therapeutics against SARS-CoV-2, scientists are racing to disseminate suggestions for rapidly deployable therapeutic options, including drug repurposing and repositioning strategies. Molecular dynamics (MD) simulations have provided the opportunity to make rational scientific breakthroughs in a time of crisis. Advancements in these technologies in recent years have become an indispensable tool for scientists studying protein structure, function, dynamics, interactions, and drug discovery. Integrating the structural data obtained from high-resolution methods with MD simulations has helped in comprehending the process of infection and pathogenesis, as well as the SARS-CoV-2 maturation in host cells, in a short duration of time. It has also guided us to identify and prioritize drug targets and new chemical entities, and to repurpose drugs. Here, we discuss how MD simulation has been explored by the scientific community to accelerate and guide translational research on SARS-CoV-2 in…

Abstract Hydrotropes are small amphiphilic molecules which help in solubilizing hydrophobic entities in aqueous medium. Recent experimental investigation has provided convincing evidences that, adenosine triphosphate (ATP), besides being an energy currency of cell , also can act as hydrotrope to inhibit the formation of protein condensates. In this work, we have designed computer simulations of prototypical macromolecules in aqueous ATP solution to dissect the molecular mechanism underlying ATP’s newly discovered role as a hydrotrope. The simulation demonstrates that ATP can unfold a single-chain of hydrophobic macromolecule as well as can disrupt the aggregation process of a hydrophobic assembly. Moreover, the introduction of charges in the macromolecule is found to reinforce ATP’s disaggregation effects in a synergistic fashion, a behaviour reminiscent of recent experimental observation of pronounced hydrotropic action of ATP in intrinsically disordered proteins. A molecular analysis indicates that this new-found ability of ATP are ingrained in its propensity of preferential…

Bottlebrush polymers (BBPs), composed of relatively short polymeric side chains densely grafted on a polymer backbone, exhibit many unique characteristics and hold promise for a variety of applications. This Perspective focuses on environmentally induced shape-changing behavior of BBPs at interface and in solution, particularly worm/star-globule shape transitions. While BBPs with a single type of homopolymer or random copolymer side chains have been shown to undergo pronounced worm-to-globule shape changes in response to external stimuli, the collapsed brushes are unstable and prone to aggregation. By introducing a second, solvophilic polymer into the side chains, either as a distinct type of side chain or as the outer block of block copolymer side chains, the collapsed brushes not only are stabilized but also create unimolecular micellar nanostructures, which can be used for, e.g., encapsulation and delivery of substances. The current challenges in the design, synthesis, and characterization of stimuli-responsive shape-changing BBPs are discussed.

Mass transfer across a liquid-repelling gas permeable membrane is influenced by the state(s) of the liquid-vapor interface(s) on the surface of the membrane, the pore geometry, and the solid-fluid interactions inside the membrane. By tuning the different local contributions, it is possible to enhance the temperature difference-driven mass flux across the membrane for a constant driving force. Non-equilibrium molecular dynamics simulations were used to simulate a temperature difference-driven mass flux through a gas permeable membrane with the evaporating liquid on one side and the condensing liquid on the other. Both sides were simulated for Wenzel- and Cassie-Baxter-like states. The interaction between the fluid and the solid inside the gas permeable membrane varied between the wetting angles of θ = 125° and θ = 103°. For a constant driving force, the Cassie-Baxter state led to an increased mass flux of almost 40% in comparison to the Wenzel state (given a small pore resistance). This difference was caused by an insufficient supply of vapor particles at the pore entrance in the…

nanoprecipitation. The internal morphology, porosity, and mechanical properties of the LNPs were analyzed with electron tomography (ET), small-angle X-ray scattering (SAXS), atomic force microscopy (AFM), and intermodulation AFM (ImAFM). We found that aqueous acetone resulted in smaller LNPs with higher uniformity compared to aqueous THF, mainly ascribing to stronger solvent-lignin interactions as suggested by MD simulation results and confirmed with aqueous 1,4-dioxane (DXN) and aqueous dimethyl sulfoxide (DMSO). More importantly, we report that both LNPs were compact particles with relatively homogeneous density distribution and very low porosity in the internal structure. The stiffness of the particles was independent of the size, and the Young's modulus was in the range of 0.3-4 GPa. Overall, the fundamental understandings of LNPs gained in this study are essential for the design of LNPs with optimal performance in applications.

Surfactants are amphiphilic molecules that are widely used in consumer products, industrial processes, and biological applications. A critical property of a surfactant is the critical micelle concentration (CMC), which is the concentration at which surfactant molecules undergo cooperative self-assembly in solution. Notably, the primary method to obtain CMCs experimentally-tensiometry-is laborious and expensive. In this study, we show that graph convolutional neural networks (GCNs) can predict CMCs directly from the surfactant molecular structure. In particular, we developed a GCN architecture that encodes the surfactant structure in the form of a molecular graph and trained it using experimental CMC data. We found that the GCN can predict CMCs with higher accuracy on a more inclusive data set than previously proposed methods and that it can generalize to anionic, cationic, zwitterionic, and nonionic surfactants using a single model. Molecular saliency maps revealed how atom types and surfactant molecular substructures contribute to CMCs and found this behavior to be in agreement…

, particularly, when looking into their bulk structural features. The article does not aim at being comprehensive but instead focuses on selected topics such as short- and intermediate-range order, the constraints on force field requirements, and other details that make the high- and low-temperature ionic melts in some ways similar but in others diametrically opposite.

Abstract The structural and biochemical studies of the SARS-CoV-2 spike glycoproteins and complexes with highly potent antibodies have revealed multiple conformation-dependent epitopes highlighting the link between conformational plasticity of spike proteins and capacity for eliciting specific binding and broad neutralization responses. In this study, we used coevolutionary analysis, molecular simulations, and perturbation-based hierarchical network modeling of the SARS-CoV-2 S complexes with H014, S309, S2M11 and S2E12 antibodies targeting distinct epitopes to explore molecular mechanisms underlying binding-induced modulation of dynamics, stability and allosteric signaling in the spike protein trimers. The results of this study revealed key regulatory centers that can govern allosteric interactions and communications in the SARS-CoV-2 spike proteins. Through coevolutionary analysis of the SARS-CoV-2 spike proteins, we identified highly coevolving hotspots and functional clusters forming coevolutionary networks. The results revealed significant coevolutionary couplings between…

The rapidly growing body of structural and biochemical studies of the SARS-CoV-2 spike glycoprotein has revealed a variety of distinct functional states with radically different arrangements of the receptor-binding domain, highlighting a remarkable function-driven conformational plasticity and adaptability of the spike proteins. In this study, we examined molecular mechanisms underlying conformational and dynamic changes in the SARS-CoV-2 spike mutant trimers through the lens of dynamic analysis of allosteric interaction networks and atomistic modeling of signal transmission. Using an integrated approach that combined coarse-grained molecular simulations, protein stability analysis, and perturbation-based modeling of residue interaction networks, we examined how mutations in the regulatory regions of the SARS-CoV-2 spike protein can differentially affect dynamics and allosteric signaling in distinct functional states. The results of this study revealed key functional regions and regulatory centers that govern collective dynamics, allosteric interactions, and control signal…

C≡N and C-D stretches complicates the spectral response but does not prevent its effective utilization. Time-resolved two-dimensional (2D) IR spectroscopy can be performed on a mixture of acetonitrile isotopologues and much can be learned about the structural dynamics of various species in these formulations.

Binding free energy calculations have become increasingly valuable to drive decision making in drug discovery projects. However, among other issues, inadequate sampling can reduce accuracy, limiting the value of the technique. In this paper, we apply absolute binding free energy calculations to ligands binding to T4 lysozyme L99A and HSP90 using equilibrium and nonequilibrium approaches. We highlight sampling problems encountered in these systems, such as slow side chain rearrangements and slow changes of water placement upon ligand binding. These same types of challenges are also likely to show up in other protein-ligand systems, and we propose some strategies to diagnose and test for such problems in alchemical free energy calculations. We also explore similarities and differences in how the equilibrium and the nonequilibrium approaches handle these problems. Our results show the large amount of work still to be done to make free energy calculations robust and reliable and provide insight for future research in this area.

Within condensed matter, single fluorophores are sensitive probes of their chemical environments, but it is difficult to use their limited photon budget to image precisely their positions, 3D orientations, and rotational diffusion simultaneously. We demonstrate the polarized vortex point spread function (PSF) for measuring these parameters, including characterizing the anisotropy of a molecule's wobble, simultaneously from a single image. Even when imaging dim emitters (∼500 photons detected), the polarized vortex PSF can obtain 12 nm localization precision, 4°-8° orientation precision, and 26° wobble precision. We use the vortex PSF to measure the emission anisotropy of fluorescent beads, the wobble dynamics of Nile red (NR) within supported lipid bilayers, and the distinct orientation signatures of NR in contact with amyloid-beta fibrils, oligomers, and tangles. The unparalleled sensitivity of the vortex PSF transforms single-molecule microscopes into nanoscale orientation imaging spectrometers, where the orientations and wobbles of individual probes reveal structures and…

During infection the SARS-CoV-2 virus fuses its viral envelope with cellular membranes of its human host. The viral spike (S) protein mediates both the initial contact with the host cell and the subsequent membrane fusion. Proteolytic cleavage of S at the S2' site exposes its fusion peptide (FP) as the new N-terminus. By binding to the host membrane, the FP anchors the virus to the host cell. The reorganization of S2 between virus and host then pulls the two membranes together. Here we use molecular dynamics (MD) simulations to study the two core functions of the SARS-CoV-2 FP: to attach quickly to cellular membranes and to form an anchor strong enough to withstand the mechanical force during membrane fusion. In eight 10 μs long MD simulations of FP in proximity to endosomal and plasma membranes, we find that FP binds spontaneously to the membranes and that binding proceeds predominantly by insertion of two short amphipathic helices into the membrane interface. Connected via a flexible linker, the two helices can bind the membrane independently, yet binding of one promotes the…

Polymer band gap is one of the most important properties associated with electric conductivity. In this work, the machine learning model called support vector regression (SVR) was developed to predict the polymer band gap, where the training data of the polymer band gap were obtained from DFT computation while the descriptors were generated from Dragon. After feature selection with the maximum relevance minimum redundancy, the SVR model using 16 key features as inputs gave the optimal performance for predicting polymer band gaps. The determination coefficient ( R 2 ) of the SVR model between the DFT computations and SVR predictions of polymer band gaps reached as high as 0.824 for the leave-one-out cross-validation and 0.925 for the independent test. Besides, the 16 key features were explored through correlation analysis and sensitivity analysis. The available model can be used to screen out the polymers with targeted band gaps before experiments, which is very helpful for rapid design of new polymers.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects human cells by binding its spike (S) glycoproteins to angiotensin-converting enzyme 2 (ACE2) receptors and causes the coronavirus disease 2019 (COVID-19). Therapeutic approaches to prevent SARS-CoV-2 infection are mostly focused on blocking S-ACE2 binding, but critical residues that stabilize this interaction are not well understood. By performing all-atom molecular dynamics (MD) simulations, we identified an extended network of salt bridges, hydrophobic and electrostatic interactions, and hydrogen bonds between the receptor-binding domain (RBD) of the S protein and ACE2. Mutagenesis of these residues on the RBD was not sufficient to destabilize binding but reduced the average work to unbind the S protein from ACE2. In particular, the hydrophobic end of RBD serves as the main anchor site and is the last to unbind from ACE2 under force. We propose that blocking the hydrophobic surface of RBD via neutralizing antibodies could prove to be an effective strategy to inhibit S-ACE2 interactions.

Understanding the operation of neurons and synapses is essential to reproducing biological computation. Building artificial neuromorphic networks opens the door to a new generation of faster and low-energy-consuming electronic circuits for computation. The main candidates to imitate the natural biocomputation processes, such as the generation of action potentials and spiking, are memristors. Generally, the study of the performance of material neuromorphic elements is done by the analysis of time transient signals. Here, we present an analysis of neural systems in the frequency domain by small-amplitude ac impedance spectroscopy. We start from the constitutive equations for the conductance and memory effect, and we derive and classify the impedance spectroscopy spectra. We first provide a general analysis of a memristor and demonstrate that this element can be expressed as a combination of simple parts. In particular, we derive a basic equivalent circuit where the memory effect is represented by an RL branch. We show that this ac model is quite general and describes the…

Liquid–liquid phase separation (LLPS) of proteins and nucleic acids to form membraneless cellular compartments is considered to be involved in various biological functions. The RNA-binding protein fused in sarcoma (FUS) undergoes LLPS in vivo and in vitro . Here, we investigated the effects of pressure and temperature on the LLPS of FUS by high-pressure microscopy and high-pressure UV/vis spectroscopy. The phase-separated condensate of FUS was obliterated with increasing pressure but was observed again at a higher pressure. We generated a pressure–temperature phase diagram that describes the phase separation of FUS and provides a general understanding of the thermodynamic properties of self-assembly and phase separation of proteins. FUS has two types of condensed phases, observed at low pressure (LP-LLPS) and high pressure (HP-LLPS). The HP-LLPS state was more condensed and exhibited lower susceptibility to dissolution by 1,6-hexanediol and karyopherin-β2 than the LP-LLPS state. Moreover, molecular dynamic simulations revealed that electrostatic interactions were destabilized,…

Spiro rhodamine (Rho)-perylene (Pery) electron donor–acceptor dyads were prepared to study the spin–orbit charge transfer intersystem crossing (SOCT-ISC) in these rigid and sterically congested molecular systems. The electron-donor Rho (lactam form) moiety is attached via the N–C bond to the electron acceptor at either 1- or 3-position of the Pery moiety ( Rho-Pery-1 and Rho-Pery-3 ). Severe torsion of the Pery moiety in Rho-Pery-1 was observed. The fluorescence of the two dyads is significantly quenched in polar solvents, and the singlet oxygen quantum yields (Φ Δ ) are strongly dependent on solvent polarity (4–36%). Femtosecond transient absorption spectra demonstrate that charge separation (CS) takes 0.51 ps in Rho-Pery-1 and 5.75 ps in Rho-Pery-3, and the charge recombination (CR)-induced ISC is slow (>3 ns). Nanosecond transient absorption spectra indicate that the formation of triplet states via SOCT-ISC takes 24–75 ns for Rho-Pery-1 and 6–15 ns for Rho-Pery-3, and the distorted π-framework of the Pery moiety results in a shorter triplet lifetime of 19.9 vs 291 μs for the…

Mechanical properties of aerogels are controlled by the connectivity of their network. In this paper, in order to study these properties, computational models of silica aerogels with different morphological entities have been generated by means of the diffusion-limited cluster–cluster aggregation (DLCA) algorithm. New insights into the influence of the model parameters on the generated aerogel structures and on the finite deformation under mechanical loads are provided. First, the structural and fractal properties of the modeled aerogels are investigated. The dependence of morphological properties such as the particle radius and density on these properties is studied. The results are correlated with experimental small-angle X-ray scattering (SAXS) data of a silica aerogel. The DLCA models of silica aerogels are analyzed for their mechanical properties with finite element simulations. There, the aerogel particles are modeled as nodes and the interparticle bonds as beam elements to account for bond stretching, bending, and torsion. The scaling relation between the elastic moduli E and…

Li-ion-hopping conduction is known to occur in certain highly concentrated electrolytes, and this conduction mode is effective for achieving lithium batteries with high rate capabilities. Herein, we investigated the effects of the solvent structure on the hopping conduction of Li ions in highly concentrated LiBF 4 /sulfone electrolytes. Raman spectroscopy revealed that a Li + ion forms complexes with sulfone and anions, and contact ion pairs and ionic aggregates are formed in the highly concentrated electrolytes. Li + exchanges ligands (sulfone and BF 4 – ) rapidly to produce unusual hopping conduction in highly concentrated electrolytes. The structure of the solvent significantly influences the hopping conduction process. We measured the self-diffusion coefficients of Li + ( D Li ), anions ( D anion ), and sulfone solvents ( D sol ) in electrolytes. The ratio of the self-diffusion coefficients ( D Li / D sol ) tended to be higher for cyclic sulfones (sulfolane and 3-methylsulfolane) than for acyclic sulfones, which suggests that cyclic sulfone molecules facilitate Li-ion hopping.…

. This Review Article provides perspectives and initiates future studies to investigate the role of neuropeptides as metal chelators in neurodegenerative diseases.

The increasing realization of the prevalence of liquid–liquid phase separation (LLPS) across multiple length scales of biological constructs, from intracellular membraneless organelles to extracellular load-bearing tissues, has raised intriguing questions about intermolecular interactions regulating LLPS at the atomic level. Squid-beak derived histidine (His)- and tyrosine (Tyr)-rich peptides (HB peps ) have recently emerged as suitable short model peptides to precisely assess the roles of peptide motifs and single residues on the phase behavior and material properties of microdroplets obtained by LLPS. In this study, by systematically introducing single mutations in an HB pep, we have identified specific sticker residues that attract peptide chains together. We find that His and Tyr residues located near the sequence termini drive phase separation, forming interaction nodes that stabilize microdroplets. Combining quantum chemistry simulations with NMR studies, we predict atomic-level bond geometries and uncover inter-residue supramolecular interactions governing LLPS. These results…

The photophysical properties, especially the intersystem crossing (ISC) of two heavy-atom-free BODIPY derivatives with twisted π-conjugated frameworks (benzo[ b ]-fused BODIPY, BDP-B; and [ a ]phenanthrene-fused BODIPY, BDP-P ), are studied with steady-state and time-resolved optical and electron paramagnetic resonance (TREPR) spectroscopic methods as well as with ADC(2) theoretical investigations. Interestingly, BDP-B has a planar π-conjugation framework, but it displays weaker UV–vis absorption (ε = 3.8 × 10 4 M –1 cm –1 at 569 nm) and fluorescence (Φ F < 0.1%), a short-lived singlet-excited state (fluorescence lifetime, τ F = 0.2 ns), and a long-lived triplet state (τ T = 132.3 μs). In comparison, the more twisted BDP-P shows stronger UV–vis absorption (ε = 9.8 × 10 4 M –1 cm –1 at 640 nm) and fluorescence (Φ F = 70%), longer singlet-excited-state lifetime (τ F = 6.4 ns), and shorter triplet-state lifetime (τ T = 18.9 μs). In contrast to helicenes (Φ T = ca. 90%), the ISC of BDP-P and BDP-B is nonefficient (Φ T < 23%). The electron spin selectivity of the ISC of the derivatives…

Active colloids are a synthetic analogue of biological microorganisms that consume external energy to swim through viscous fluids. Such motion requires breaking the symmetry of the fluid flow in the vicinity of a particle; however, it is challenging to understand how surface and shape anisotropies of the colloid lead to a particular trajectory. Here, we attempt to deconvolute the effects of particle shape and surface anisotropy on the propulsion of model ellipsoids in alternating current (AC) electric fields. We first introduce a simple process for depositing metal patches of various shapes on the surfaces of ellipsoidal particles. We show that the shape of the metal patch is governed by the assembled structure of the ellipsoids on the substrate used for physical vapor deposition. Under high-frequency AC electric field, ellipsoids dispersed in water show linear, circular, and helical trajectories which depend on the shapes of the surface patches. We demonstrate that features of the helical trajectories such as the pitch and diameter can be tuned by varying the degree of patch…

Accurate prediction of alkane phase transitions involving solids is needed to prevent catastrophic pipeline blockages, improve lubrication formulations, smart insulation, and energy storage, as well as bring fundamental understanding to processes such as artificial morphogenesis. However, simulation of these transitions is challenging and therefore often omitted in force field development. Here, we perform a series of benchmarks on seven representative molecular dynamics models (TraPPE, PYS, CHARMM36, L-OPLS, COMPASS, Williams, and the newly optimized Williams 7B), comparing with experimental data for liquid properties, liquid–solid, and solid–solid phase transitions of two prototypical alkanes, n -pentadecane (C 15 ) and n -hexadecane (C 16 ). We find that existing models overestimate the melting points by up to 34 K, with PYS and Williams 7B yielding the most accurate results deviating only 2 and 3 K from the experiment. We specially design order parameters to identify crystal–rotator phase transitions in alkanes. United-atom models could only produce a rotator phase with complete…

While the pervasiveness of allostery in proteins is commonly accepted, we further show the generic nature of allosteric mechanisms by analyzing here transmembrane ion-channel viroporin 3a and RNA-dependent RNA polymerase (RdRp) from SARS-CoV-2 along with metabolic enzymes isocitrate dehydrogenase 1 (IDH1) and fumarate hydratase (FH) implicated in cancers. Using the previously developed structure-based statistical mechanical model of allostery (SBSMMA), we share our experience in analyzing the allosteric signaling, predicting latent allosteric sites, inducing and tuning targeted allosteric response, and exploring the allosteric effects of mutations. This, yet incomplete list of phenomenology, forms a complex and unique allosteric territory of protein function, which should be thoroughly explored. We propose a generic computational framework, which not only allows one to obtain a comprehensive allosteric control over proteins but also provides an opportunity to approach the fragment-based design of allosteric effectors and drug candidates. The advantages of allosteric drugs over…

High Resolution Image Download MS PowerPoint Slide Hydrophobic deep eutectic solvents (DESs) have recently gained much attention as water-immiscible solvents for a wide range of applications. However, very few studies exist in which the hydrophobicity of these DESs is quantified. In this work, the interfacial properties of hydrophobic DESs with water were computed at various temperatures using molecular dynamics simulations. The considered DESs were tetrabutylammonium chloride–decanoic acid (TBAC–dec) with a molar ratio of 1:2, thymol–decanoic acid (Thy–dec) with a molar ratio of 1:2, and dl -menthol–decanoic acid (Men–dec) with a molar ratio of 2:1. The following properties were investigated in detail: interfacial tensions, water-in-DES solubilities (and salt-in-water solubilities for TBAC–dec/water), density profiles, and the number densities of hydrogen bonds. Different ionic charge scaling factors were used for TBAC–dec. Thy–dec and Men–dec showed a high level of hydrophobicity with negligible computed water-in-DES solubilities. For charge scaling factors of 0.7 and 1 for the…