The 50 most-cited articles in The Journal of Physical Chemistry B, 2024

Atomistic molecular dynamics (MD) simulations have become an indispensable tool for investigating the structure, dynamics, and energetics of biomolecules. Continual optimization of software algorithms and hardware has enabled investigators to access biologically relevant time scales in feasible amounts of computing time. Given the widespread use and utility of MD simulations, there is considerable interest in learning essential skills in performing them. Here, we present a set of introductory tutorials for performing MD simulations of proteins in the popular, open-source GROMACS package. Three exercises are detailed, including simulating a single protein, setting up a protein complex, and performing umbrella sampling simulations to model the unfolding of a short polypeptide. Essential features and input settings are illustrated throughout. The purpose of these tutorials is to provide new users with a general understanding of foundational workflows, from which they can design their own simulations.

Since its inception nearly a half century ago, CHARMM has been playing a central role in computational biochemistry and biophysics. Commensurate with the developments in experimental research and advances in computer hardware, the range of methods and applicability of CHARMM have also grown. This review summarizes major developments that occurred after 2009 when the last review of CHARMM was published. They include the following: new faster simulation engines, accessible user interfaces for convenient workflows, and a vast array of simulation and analysis methods that encompass quantum mechanical, atomistic, and coarse-grained levels, as well as extensive coverage of force fields. In addition to providing the current snapshot of the CHARMM development, this review may serve as a starting point for exploring relevant theories and computational methods for tackling contemporary and emerging problems in biomolecular systems. CHARMM is freely available for academic and nonprofit research at https://academiccharmm.org/program.

High Resolution Image Download MS PowerPoint Slide Networks of tryptophan (Trp)─an aromatic amino acid with strong fluorescence response─are ubiquitous in biological systems, forming diverse architectures in transmembrane proteins, cytoskeletal filaments, subneuronal elements, photoreceptor complexes, virion capsids, and other cellular structures. We analyze the cooperative effects induced by ultraviolet (UV) excitation of several biologically relevant Trp mega-networks, thus giving insights into novel mechanisms for cellular signaling and control. Our theoretical analysis in the single-excitation manifold predicts the formation of strongly superradiant states due to collective interactions among organized arrangements of up to >10 5 Trp UV-excited transition dipoles in microtubule architectures, which leads to an enhancement of the fluorescence quantum yield (QY) that is confirmed by our experiments. We demonstrate the observed consequences of this superradiant behavior in the fluorescence QY for hierarchically organized tubulin structures, which increases in different geometric…

Aromatic residues can participate in various biomolecular interactions, such as π-π, cation-π, and CH-π interactions, which are essential for protein structure and function. Here, we re-evaluate the geometry and energetics of these interactions using quantum mechanical (QM) calculations, focusing on pairwise interactions involving the aromatic amino acids Phe, Tyr, and Trp and the cationic amino acids Arg and Lys. Our findings reveal that π-π interactions, while energetically favorable, are less abundant in structured proteins than commonly assumed and are often overshadowed by previously underappreciated, yet prevalent, CH-π interactions. Cation-π interactions, particularly those involving Arg, show strong binding energies and a specific geometric preference toward stacked conformations, despite the global QM minimum, suggesting that a rather perpendicular T-shape conformation should be more favorable. Our results support a more nuanced understanding of protein stabilization via interactions involving aromatic residues. On the one hand, our results challenge the traditional…

New functionality is added to the LAMMPS molecular simulation package, which increases the versatility with which LAMMPS can interface with supporting software and manipulate information associated with bonded force fields. We introduce the "type label" framework that allows atom types and their higher-order interactions (bonds, angles, dihedrals, and impropers) to be represented in terms of the standard atom type strings of a bonded force field. Type labels increase the human readability of input files, enable bonded force fields to be supported by the OpenKIM repository, simplify the creation of reaction templates for the REACTER protocol, and increase compatibility with external visualization tools, such as VMD and OVITO. An introductory primer on the forms and use of bonded force fields is provided to motivate this new functionality and serve as an entry point for LAMMPS and OpenKIM users unfamiliar with bonded force fields. The type label framework has the potential to streamline modeling workflows that use LAMMPS by increasing the portability of software, files, and scripts…

Human serum albumin (HSA) acts as a repository and transporter of substances in the blood. An abnormal concentration may indicate the occurrence of liver- and kidney-related diseases, which has attracted people to investigate the precise quantification of HSA in body fluids. Fluorescent probes can combine with HSA covalently or noncovalently to quantify HSA in urine and plasma. Moreover, probes combined with HSA can improve its photophysical properties; probe-HSA has been applied in real-time monitoring and photothermal and photodynamic therapy in vivo . This Review will introduce fluorescent probes for quantitative HSA according to the three reaction mechanisms of spatial structure, enzymatic reaction, and self-assembly and systematically introduce the application of probes combined with HSA in disease imaging and phototherapy. It will help develop multifunctional applications for HSA probes and provide assistance in the early diagnosis and treatment of diseases.

High Resolution Image Download MS PowerPoint Slide In modern drug discovery, virtual ligand screening (VLS) is frequently applied to identify possible hits before experimental testing and refinement due to its cost-effective nature for large compound libraries. For decades, efforts have been devoted to developing VLS methods with high accuracy. These include the state-of-the-art FINDSITE suite of approaches FINDSITE comb2.0, FRAGSITE, and FRAGSITE2 and the meta version FRAGSITE comb that were developed in our lab. These methods combine ligand homology modeling (LHM), traditional ligand similarity methods, and more recently machine learning approaches to rank ligands and have proven to be superior to most recent deep learning and large language model-based approaches. Here, we describe further improvements to our previous best methods by combining the Morgan fingerprint (MF) with the originally used PubChem fingerprint and FP2 fingerprint. We then benchmarked FINDSITE comb2.0M, FRAGSITE M, FRAGSITE2 M, and the composite meta-approach FRAGSITE combM . On the 102 target DUD-E set, the…

CO 2 capture technology is one of the most important technical methods for significantly mitigating CO 2 emissions in a low-carbon context. The recent invention of mixed absorbents comprising poly(ethylenimine) (PEI) and ionic liquids (ILs) provides a novel strategy for efficiently capturing CO 2, and this has garnered widespread attention. However, the intermolecular interactions between the IL and other constituents during the CO 2 absorption process remain unclear. In this present work, a series of density functional theory (DFT) calculations and molecular dynamics simulations were conducted to investigate the positive role of IL in CO 2 capture by PEI. The results showed that the formation of hydrogen bonds between the IL anion and the amino groups of PEI primarily drives the addition of IL to PEI. During the CO 2 absorption process, the IL anion not only can absorb CO 2 but also exerts a dehydrogenation effect on the amino group of PEI, facilitating enhanced interaction between PEI and CO 2 . Additionally, the IL substantially reduces the viscosity of PEI, promoting the…

Very few drugs have the necessary physicochemical properties to cross the skin's main permeability barrier, the stratum corneum (SC), in sufficient amounts. Propylene glycol (PG) is a chemical penetration enhancer that could be included in topical formulations in order to overcome the barrier properties of the skin and facilitate the transport of drugs across it. Experiments have demonstrated that PG increases the mobility and disorder of SC lipids and may extract cholesterol from the SC, but little is known about the molecular mechanisms of drug permeation enhancement by PG. In this work, we have performed molecular dynamics (MD) simulations to investigate the molecular-level effects of PG on the structure and properties of model SC lipid bilayers. The model bilayers were simulated in the presence of PG concentrations over the range of 0-100% w/w PG, using both an all-atom and a united atom force field. PG was found to localize in the hydrophilic headgroup regions at the bilayer interface, to occupy the lipid-water hydrogen-bonding sites, and to slightly increase lipid tail…

In this study, we explore the impact of alkali metal ions (Li+, Na+, K+, Rb+, and Cs+) on the hydration structure of water using molecular dynamics simulations carried out with the MB-nrg potential energy functions (PEFs). Our analyses include radial distribution functions, coordination numbers, dipole moments, and infrared spectra of water molecules, calculated as a function of solvation shells. The results collectively indicate a highly local influence of all the alkali metal ions on the hydrogen-bond network established by the surrounding water molecules, with the smallest and most densely charged Li+ ion exerting the most pronounced effect. Remarkably, the MB-nrg PEFs demonstrate excellent agreement with available experimental data for the position and size of the first solvation shells, underscoring their potential as predictive models for realistic simulations of ionic aqueous solutions across various thermodynamic conditions and environments.

Colvars is an open-source C++ library that provides a modular toolkit for collective-variable-based molecular simulations. It allows practitioners to easily create and implement descriptors that best fit a process of interest and to apply a wide range of biasing algorithms in collective variable space. This paper reviews several features and improvements to Colvars that were added since its original introduction. Special attention is given to contributions that significantly expanded the capabilities of this software or its distribution with major MD simulation packages. Collective variables can now be optimized either manually or by machine-learning methods, and the space of descriptors can be explored interactively using the graphical interface included in VMD. Beyond the spatial coordinates of individual molecules, Colvars can now apply biasing forces to mesoscale structures and alchemical degrees of freedom and perform simulations guided by experimental data within ensemble averages or probability distributions. It also features advanced computational schemes to boost the…

GENeralized-Ensemble SImulation System (GENESIS) is a molecular dynamics (MD) software developed to simulate the conformational dynamics of a single biomolecule, as well as molecular interactions in large biomolecular assemblies and between multiple biomolecules in cellular environments. To achieve the latter purpose, the earlier versions of GENESIS emphasized high performance in atomistic MD simulations on massively parallel supercomputers, with or without graphics processing units (GPUs). Here, we implemented multiscale MD simulations that include atomistic, coarse-grained, and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. They demonstrate high performance and are integrated with enhanced conformational sampling algorithms and free-energy calculations without using external programs except for the QM programs. In this article, we review new functions, molecular models, and other essential features in GENESIS version 2.1 and discuss ongoing developments for future releases.

High Resolution Image Download MS PowerPoint Slide The disaccharide trehalose is generally acknowledged as a superior stabilizer of proteins and other biomolecules in aqueous environments. Despite many theories aiming to explain this, the stabilization mechanism is still far from being fully understood. This study compares the stabilizing properties of trehalose with those of the structurally similar disaccharide sucrose. The stability has been evaluated for the two proteins, lysozyme and myoglobin, at both low and high temperatures by determining the glass transition temperature, T g, and the denaturation temperature, T den . The results show that the sucrose-containing samples exhibit higher T den than the corresponding trehalose-containing samples, particularly at low water contents. The better stabilizing effect of sucrose at high temperatures may be explained by the fact that sucrose, to a greater extent, binds directly to the protein surface compared to trehalose. Both sugars show T den elevation with an increasing sugar-to-protein ratio, which allows for a more complete sugar…

The structural diversity of different lipid species within the membrane defines its biophysical properties such as membrane fluidity, phase transition, curvature, charge distribution, and tension. Environment-sensitive probes, which change their spectral properties in response to their surrounding milieu, have greatly contributed to our understanding of such biophysical properties. To realize the full potential of these probes and avoid misinterpretation of their spectral responses, a detailed investigation of their fluorescence characteristics in different environments is necessary. Here, we examined the fluorescence lifetime of two newly developed membrane order probes, NR12S and NR12A, in response to alterations in their environments such as the degree of lipid saturation, cholesterol content, double bond position and configuration, and phospholipid headgroup. As a comparison, we investigated the lifetime sensitivity of the membrane tension probe Flipper in these environments. Applying fluorescence lifetime imaging microscopy (FLIM) in both model membranes and biological…

Naturally occurring cellulose Iβ with its characteristic parallel orientation of cellulose chains is less stable than cellulose II, in which neighboring pairs of chains are oriented antiparallel to each other. While the distinct hydrogen-bond patterns of these two cellulose crystal forms are well established, the energetic role of the hydrogen bonds for crystal stability, in comparison to the van der Waals (vdW) and overall electrostatic interactions in the crystals, is a matter of current debate. In this article, we investigate the relative stability of celluloses Iβ and II in energy minimizations with classical force fields. We find that the larger stability of cellulose II results from clearly stronger electrostatic interchain energies that are only partially compensated for by stronger vdW interchain energies in cellulose Iβ. In addition, we show that a multipole description of hydrogen bonds that includes the COH groups of donor and acceptor oxygen atoms leads to consistent interchain hydrogen-bond energies that account for roughly 70% and 75% of the interchain electrostatics…

High Resolution Image Download MS PowerPoint Slide Phosphate glasses containing Nd 3+, Gd 3+, and Yb 3+ as lanthanide ions are attractive for applications in laser materials, phototherapy lamps, and solar spectral converters. The composition–structure–property relation in this type of glass system is thus of interest from fundamental and applied perspectives. In this work, the impact of the differing ionic radius of Nd 3+, Gd 3+, and Yb 3+ and consequent field strength on the physical properties of phosphate glasses is investigated, focusing ultimately on thermal expansion effects. The glasses were made by melting with a fixed concentration of the lanthanide ions having 50P 2 O 5 –46BaO–4Ln 2 O 3 nominal compositions (mol %) with Ln = Nd, Gd, and Yb. The investigation encompassed measurements by X-ray diffraction (XRD), optical spectroscopy, density, X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and dilatometry. XRD supported the amorphous nature of the glasses, whereas absorption and photoluminescence spectra showed the optical features of the Nd 3+, Gd 3+, and Yb 3+…

Deep eutectic solvents have attracted considerable attention due to their unique properties and their potential to replace conventional solvents in diverse applications, such as catalysis, energy storage, and green chemistry. However, despite their broad use, the microscopic mechanisms governing solvation dynamics and the role of hydrogen bonding in deep eutectic solvents remain insufficiently understood. In this article, we present our contributions toward unravelling the micro heterogeneity within deep eutectic solvents by combining vibrational Stark spectroscopy and two-dimensional infrared spectroscopy with molecular dynamics simulations. Our findings demonstrate how the composition, constituents, and addition of water significantly influence the heterogeneous hydrogen bonding network and solvent dynamics within these systems. These insights provide valuable guidance for the design of next-generation solvents tailored to specific applications. By integrating experimental and computational approaches, this work sheds light on the intricate relationship between solvation dynamics…

Force fields are a key component of physics-based molecular modeling, describing the energies and forces in a molecular system as a function of the positions of the atoms and molecules involved. Here, we provide a review and scientific status report on the work of the Open Force Field (OpenFF) Initiative, which focuses on the science, infrastructure and data required to build the next generation of biomolecular force fields. We introduce the OpenFF Initiative and the related OpenFF Consortium, describe its approach to force field development and software, and discuss accomplishments to date as well as future plans. OpenFF releases both software and data under open and permissive licensing agreements to enable rapid application, validation, extension, and modification of its force fields and software tools. We discuss lessons learned to date in this new approach to force field development. We also highlight ways that other force field researchers can get involved, as well as some recent successes of outside researchers taking advantage of OpenFF tools and data.

We present software infrastructure for the design and testing of new quantum mechanical/molecular mechanical and machine-learning potential (QM/MM-ΔMLP) force fields for a wide range of applications. The software integrates Amber's molecular dynamics simulation capabilities with fast, approximate quantum models in the xtb package and machine-learning potential corrections in DeePMD-kit. The xtb package implements the recently developed density-functional tight-binding QM models with multipolar electrostatics and density-dependent dispersion (GFN2-xTB), and the interface with Amber enables their use in periodic boundary QM/MM simulations with linear-scaling QM/MM particle-mesh Ewald electrostatics. The accuracy of the semiempirical models is enhanced by including machine-learning correction potentials (ΔMLPs) enabled through an interface with the DeePMD-kit software. The goal of this paper is to present and validate the implementation of this software infrastructure in molecular dynamics and free energy simulations. The utility of the new infrastructure is demonstrated in…

Fluorescence concentration quenching occurs when increasing molecular concentration of fluorophores results in a decreasing fluorescence quantum yield. Even though this phenomenon has been studied for decades, its mechanisms and signatures are not yet fully understood. The complexity of the problem arises due to energy migration and trapping in huge networks of molecules. Most of the available theoretical work focuses on integral quantities like fluorescence quantum yield and mean excitation lifetime. In this work, we present a numerical study of the fluorescence decay kinetics of three-dimensional and two-dimensional molecular systems. We investigate the differences arising from the variations in models of trap formations. We also analyze the influence of the molecular orientations to the fluorescence decay kinetics. We compare our results to the well-known analytical models and discuss their ranges of validity. Our findings suggest that the analytical models can provide inspiration for different ways of approximating the fluorescence kinetics, yet more detailed analysis of the…

Plastic materials are ubiquitous and raise concerns about their impact on health and the environment. To address these concerns, it is crucial to characterize the structural, size, and textural properties of plastics throughout their lifecycle from production to degradation. Raman spectroscopy appears as a valuable tool for this purpose, offering speed, robustness, and sensitivity to nanoscale and amorphous particles. In order to be properly used for plastics, the Raman response of reference materials needs to be carefully assessed, with the literature on such assessments being scarce. This study addresses this gap by using theoretical calculations to generate ab initio spectra for polystyrene, a reference material. The aim is to explain the origins of the spectral peaks and their consistency across various compositions and structures using linear ordered polymeric and finite amorphous models. The CRYSTAL package is employed to obtain full Raman spectra based on a careful benchmark of computational settings. While some peaks are present across all spectra and can serve for…

As demands on Li-ion battery performance increase, the need for electrolytes with high ionic conductivity and a high Li + transference number ( t Li ) becomes crucial to boost power density. Unfortunately, t Li in liquid electrolytes is typically <0.5 due to Li + migrating via a vehicular mechanism, whereby Li + diffuses along with its solvation shell, making its diffusivity slower than the counteranion. Designing liquid electrolytes where the Li + ion diffuses independently of its solvation shell is of significant interest to enhance the transference number. In this work, we elucidate how the properties of the solvent influence the Li + transport mechanism. Using classical molecular dynamics simulations, we find that a vehicular mechanism can be increasingly preferred with a decreasing solvent viscosity and increasing interaction energy between the solvent and Li + . Thus, a weaker interaction energy can enhance t Li through a solvent-exchange mechanism, ultimately improving Li-ion battery performance. Finally, metadynamics simulations show that in electrolytes where a…

Abstract Classical molecular dynamics (MD) simulations provide unmatched spatial and time resolution of protein structure and function. However, accuracy of MD simulations often depends on the quality of force field parameters and the time scale of sampling. Another limitation of conventional MD simulations is that the protonation states of titratable amino acid residues remain fixed during simulations, even though protonation state changes coupled to conformational dynamics are central to protein function. Due to the uncertainty in selecting protonation states, classical MD simulations are sometimes performed with all amino acids modeled in their standard charged states at pH 7. Here we performed and analyzed classical MD simulations on high-resolution cryo-EM structures of two membrane proteins that transfer protons by catalyzing protonation/deprotonation reactions. In simulations performed with amino acids modeled in their standard protonation state the structure diverges far from its starting conformation. In comparison, MD simulations performed with pre-determined protonation…

High Resolution Image Download MS PowerPoint Slide Nile Red is a fluorescent dye used extensively in bioimaging due to its strong solvatochromism. The photophysics underpinning Nile Red’s fluorescence has been disputed for decades, with some studies claiming that the dye fluoresces from two excited states and/or that the main emissive state is twisted and intramolecular charge-transfer (ICT) in character as opposed to planar ICT (PICT). To resolve these long-standing questions, a combined experimental and theoretical study was used to unravel the mechanism of Nile Red’s fluorescence. Time-resolved fluorescence measurements indicated that Nile Red emission occurs from a single excited state. Theoretical calculations revealed no evidence for a low-lying TICT state, with the S 1 minimum corresponding to a PICT state. Ultrafast pump–probe spectroscopic data contained no signatures associated with an additional excited state involved in the fluorescence decay of Nile Red. Collectively, these data in polar and nonpolar solvents refute dual fluorescence in Nile Red and definitively…

Using a combination of experiments and calculations, we have gained new insights into the nature of anion-cation interactions in ionic liquids (ILs). An X-ray photoelectron spectroscopy (XPS)-derived anion-dependent electrostatic interaction strength scale, determined using XPS core-level binding energies for IL cations, is presented here for 39 different anions, with at least 18 new anions included. Linear correlations of experimental XPS core-level binding energies for IL cations with (a) calculated core binding energies (ab initio molecular dynamics (AIMD) simulations were used to generate high-quality model IL structures followed by single-point density functional theory (DFT) to obtain calculated core binding energies), (b) experimental XPS core-level binding energies for IL anions, and (c) other anion-dependent interaction strength scales led to three main conclusions. First, the effect of different anions on the cation can be related to ground-state interactions. Second, the variations of anion-dependent interactions with the identity of the anion are best rationalized in…

A novel in silico drug design procedure is described targeting the Main protease (Mpro) of the SARS-CoV-2 virus. The procedure combines molecular docking, molecular dynamics (MD), and fragment molecular orbital (FMO) calculations. The binding structure and properties of Mpro were predicted for Nelfinavir (NFV), which had been identified as a candidate compound through drug repositioning, targeting Mpro. Several poses of the Mpro and NFV complexes were generated by docking, from which four docking poses were selected by scoring with FMO energy. Then, each pose was subjected to MD simulation, 100 snapshot structures were sampled from each of the generated MD trajectories, and the structures were evaluated by FMO calculations to rank the pose based on binding energy. Several residues were found to be important in ligand recognition, including Glu47, Asp48, Glu166, Asp187, and Gln189, all of which interacted strongly with NFV. Asn142 is presumably regarded to form hydrogen bonds or CH/π interaction with NFV; however, in the present calculation, their interactions were transient.…

Macromolecular crowding bridges in vivo and in vitro studies by simulating cellular complexities such as high viscosity and limited space while maintaining the experimental feasibility. Over the last two decades, the impact of macromolecular crowding on protein stability and activity has been a significant topic of study and discussion, though still lacking a thorough mechanistic understanding. This article investigates the role of associated water dynamics on protein stability and activity within crowded environments, using bromelain and Ficoll-70 as the model systems. Traditional crowding theory primarily attributes protein stability to entropic effects (excluded volume) and enthalpic interactions. However, our recent findings suggest that water structure modulation plays a crucial role in a crowded environment. In this report, we strengthen the conclusion of our previous study, i.e., rigid-associated water stabilizes proteins via entropy and destabilizes them via enthalpy, while flexible water has the opposite effect. In the process, we addressed previous shortcomings with a…

Molecular dynamics (MD) simulation is an important tool for predicting thermo-mechanical properties of polymer resins at the nanometer length scale, which is particularly important for efficient computationally driven design of advanced composite materials and structures. Because of the statistical nature of modeling amorphous materials on the nanometer length scale, multiple MD models (replicates) are typically built and simulated for statistical sampling of predicted properties. Larger replicates generally provide higher precision in the predictions but result in higher simulation times. Unfortunately, there is insufficient information in the literature to establish guidelines between MD model size and the resulting precision in predicted thermo-mechanical properties. The objective of this study was to determine the optimal MD model size of epoxy resin to balance efficiency and precision. The results show that an MD model size of 15,000 atoms provides for the fastest simulations without sacrificing precision in the prediction of mass density, elastic properties, strength, and…

High Resolution Image Download MS PowerPoint Slide Recent research and reviews on CO 2 capture methods, along with advancements in industry, have highlighted high costs and energy-intensive nature as the primary limitations of conventional direct air capture and storage (DACS) methods. In response to these challenges, deep eutectic solvents (DESs) have emerged as promising absorbents due to their scalability, selectivity, and lower environmental impact compared to other absorbents. However, the molecular origins of their enhanced thermal stability and selectivity for DAC applications have not been explored before. Therefore, the current study focuses on a comprehensive investigation into the molecular interactions within an alkaline DES composed of potassium hydroxide (KOH) and ethylene glycol (EG). Combining Fourier transform infrared (FT-IR) and quantum chemical calculations, the study reports structural changes and intermolecular interactions induced in EG upon addition of KOH and its implications on CO 2 capture. Experimental and computational spectroscopic studies confirm the…

Using theoretical techniques, the interactions between adenosine (AD) and minoxidil sulfate (MS) were studied using the DFT/M06-2X/aug-cc-pVDZ level of theory. The formation of the complex was thermodynamically favorable, so we carried out further studies. Frontier molecular orbital analysis shows that the HOMO–LUMO– gap is high (6.81 eV), which means that the complex is kinetically stable. The global reactivity parameters were also calculated to get insight about the chemical reactivity of the complex. Molecular electrostatic potential and charge analyses were carried out for the optimized complex. To study the charge transfer and inter- and intramolecular interactions present in the complex molecule, we employed natural bond orbital analysis. Noncovalent interaction (NCI) analysis along with IGMH and IRI analyses further helped us find the weak interactions. The presence of hydrogen bonds between the N atom (N 27 ) of MS and H atom (H 66 ) of AD and O atom (O 32 ) of MS and H atom (H 46 ) of AD was the main finding of these analyses. QTAIM investigation also supports this finding.…

In aqueous solutions, the impact of ions on hydrogen bond networks plays a crucial role in transport properties. We used molecular dynamics simulations to explain how ions affect viscosity through structural changes. We developed a quantitative model to describe the effect of ions on viscosity. The model comprises two parts: the addition of ions alters hydrogen bond networks, and changes in hydrogen bond networks exponentially lead to changes in viscosity. The influence of ions on hydrogen bond networks involves the following mechanisms: first, ions can disrupt the tetrahedral structures within the first solvation shell into three-coordinated structures through substitution; second, structural changes within the first shells affect the global hydrogen bond network through electrostatic forces and the hindrance of ionic volumes. By analyzing the mechanisms of how hydrogen bond networks determine viscosity through the decomposition of viscosity, we found that the proportion of potential viscosity in aqueous solutions primarily increases due to the enhancement of non-hydrogen bonding…

Molecular dynamics simulation is a powerful tool for characterizing the solution structural ensembles of cyclic peptides. However, the ability of simulation to recapitulate experimental results and make accurate predictions largely depends on the force fields used. In our work here, we evaluate the performance of seven state-of-the-art force fields in recapitulating the experimental NMR results in water of 12 benchmark cyclic peptides, consisting of 6 cyclic pentapeptides, 4 cyclic hexapeptides, and 2 cyclic heptapeptides. The results show that RSFF2+TIP3P, RSFF2C+TIP3P, and Amber14SB+TIP3P exhibit similar and the best performance, all recapitulating the NMR-derived structure information on 10 cyclic peptides. Amber19SB+OPC successfully recapitulates the NMR-derived structure information on 8 cyclic peptides. In contrast, OPLS-AA/M+TIP4P, Amber03+TIP3P, and Amber14SBonlysc+GB-neck2 could only recapitulate the NMR-derived structure information on 5 cyclic peptides, the majority of which are not well-structured.

Rational design of ionic liquids (ILs) with wide electrochemical windows (ECWs) for high-voltage cathodes is essential to elevating the energy density of current rechargeable batteries. It is significant to determine appropriate strategies for accurately predicting the ECWs of ILs. In this study, we compare the calculated ECWs based on three quantum methods, including the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) method, the ionization potential-electron affinity (IP-EA) method, and the thermodynamic method, under four unique combinations of simulation environments, and assess the discrepancies between the calculated and the experimental results of ECWs. For the three quantum methods, although HOMO-LUMO and IP-EA methods show limited prediction accuracy compared to the experimental values, they can qualitatively rank the anodic limits of anions and the cathodic limits of cations. For the thermodynamic method, we demonstrate that the highest accuracy can be achieved by considering the most rational redox reaction process. By varying the…

Water is used as the main solvent in model systems containing bioorganic molecules. Choosing the right water model is an important step in the study of the biophysical and biochemical processes that occur in cells. In the present work, we perform molecular dynamics simulations using two distinct force fields for water: the rigid model TIP4P/2005, where only intermolecular interactions are considered, and the flexible model SPC/Fw, where intramolecular interactions are also taken into account. The simulations aim to determine the effect of the inclusion of intramolecular interactions on the accuracy of calculated properties of bulk water (density and thermal expansion coefficient, self-diffusion coefficients, shear viscosity, radial distribution functions, and dielectric constant), as compared to experimental results, over a temperature range between 250 and 370 K. We find that the results of the rigid model present the smallest deviations relative to experiments for most of the calculated quantities, except for the shear viscosity of supercooled water and the water dielectric…

Polymer modification is a promising approach to enhancing the performance of asphalt binders. However, a major issue plaguing polymer mixing with asphalt is the phase separation of these two components post-mixing. In the field of polymer science, the Flory-Huggins theory has been long established as the way to describe the conditions under which a mixture is stable or unstable. This Flory-Huggins interaction parameter χ and the molecular weights of the components are required under this theory. This work uses molecular dynamics simulations to calculate χ between various polymers found in waste plastics and asphalt. The compatibility of these polymers with the asphalt binder is discussed as a function of binder composition, molecular weight, and temperature. Four common polymers (polyethylene, polystyrene, polypropylene, and polybutadiene) were tested. While none of the polymers showed good compatibility with asphalt, PE was the most compatible. Stable compatibilization of plastics with asphalt will require additives or chemical modification of the plastic.

High Resolution Image Download MS PowerPoint Slide The liquid structure of three common ionic liquids (ILs) was investigated by neutron scattering for the first time. The ILs were based on the bis(trifluoromethanesulfonyl)imide anion, abbreviated in the literature as [NTf 2 ] − or [TFSI] −, and on the following cations: 1-ethyl-3-methylimidazolium, [C 2 mim] +; 1-decyl-3-methylimidazolium, [C 10 mim] +; and trihexyl(tetradecyl)phosphonium, [P 666,14 ] + . Comparative analysis of the three ILs confirmed increased size of nonpolar nanodomains with increasing bulk of alkyl chains. It also sheds light on the cation–anion interactions, providing experimental insight into strength, directionality, and angle of hydrogen bonds between protons on the imidazolium ring, as well as H–C–P protons in [P 666,14 ] +, to oxygen and nitrogen atoms in the [NTf 2 ] − . The new Dissolve data analysis package enabled, for the first time, the analysis of neutron scattering data of ILs with long alkyl chains, in particular, of [P 666,14 ][NTf 2 ]. Results generated with Dissolve were validated by comparing…

Antimicrobial peptides (AMPs) are attractive materials for combating the antimicrobial resistance crisis because they can kill target microbes by directly disrupting cell membranes. Although thousands of AMPs have been discovered, their molecular mechanisms of action are still poorly understood. One broad mechanism for membrane disruption is the formation of membrane-spanning hydrophilic pores which can be stabilized by AMPs. In this study, we use molecular dynamics simulations to investigate the thermodynamics of pore formation in model single-component lipid membranes in the presence of one of three AMPs: aurein 1.2, melittin and magainin 2. To overcome the general challenge of modeling long time scale membrane-related behaviors, including AMP binding, clustering, and pore formation, we develop a generalizable methodology for sampling AMP-induced pore formation. This approach involves the long equilibration of peptides around a pore created with a nucleation collective variable by performing coarse-grained simulations, then backmapping equilibrated AMP-membrane configurations to…

High Resolution Image Download MS PowerPoint Slide Simulations of Density Functional Theory-based ab initio molecular dynamics (AIMD) have been performed for a series of aqueous lithium bis(trifluoromethylsulfonyl)imide (LiTFSI) solutions with concentrations ranging from salt-in-water to water-in-salt systems. Analysis of the structure of electrolytes has revealed a preference of Li + cations to interact with water molecules. In concentrated LiTFSI solutions, water molecules form small associates. The total number of hydrogen bonds (HBs) in the system decreases with salt concentrations, with bonds to water acceptors being only partially replaced by interactions with TFSI anions. Infrared (IR) spectra in the region of the O–H stretching frequency calculated from AIMD trajectories are in good agreement with experimental data. Statistics of oscillations of individual O–H bonds have shown correlations between vibrational frequencies and the structure of HBs formed by water. The changes in the IR spectrum have been related to the varying contributions of different local environments of…

Metal ions play crucial roles in protein- and ligand-mediated interactions. They not only act as catalysts to facilitate biological processes but are also important as protein structural elements. Accurately predicting metal ion interactions in computational studies has always been a challenge, and various methods have been suggested to improve these interactions. One such method is the 12–6–4 Lennard-Jones (LJ)-type nonbonded model. Using this model, it has been possible to successfully reproduce the experimental properties of metal ions in aqueous solution. The model includes induced dipole interactions typically ignored in the standard 12–6 LJ nonbonded model. In this we expand the applicability of this model to metal ion–carboxylate interactions. Using 12–6–4 parameters that reproduce the solvation free energies of the metal ions leads to an overestimation of metal ion–acetate interactions, thus, prompting us to fine-tune the model to specifically handle the latter. We also show that the standard 12–6 LJ model significantly falls short in reproducing the experimental binding…

The glass transition temperature ( T g ) is a crucial characteristic of polyimides (PIs). Developing a T g predictive model using machine learning methodologies can facilitate the design of PI structures and expedite the development process. In this investigation, a data set comprising 1257 PIs was assembled, with T g values determined using differential scanning calorimetry. 210 molecular descriptors were computed using RDKit, and subsequently, six distinct feature selection methodologies were employed to refine the descriptor set. Quantitative structure–property relationship models targeting T g ( T g -QSPR) were then constructed using five ensemble learning algorithms and one deep learning algorithm. These models exhibited high predictive accuracy and robustness, with the CATBoost model demonstrating the highest accuracy, achieving a coefficient of determination of 0.823 for the test set, a mean absolute error of 20.1 °C, and a root-mean-square error of 29.0 °C. The study identified the NumRotatableBonds descriptor as particularly influential on T g, showing a negative…

Cryoprotectants play a crucial role in preserving biological material, ensuring their viability during storage and facilitating crucial applications such as the conservation of medical compounds, tissues, and organs for transplantation. However, the precise mechanism by which cryoprotectants modulate the thermodynamic properties of water to impede the formation and growth of ice crystals, thus preventing long-term damage, remains elusive. This is evident in the use of empirically optimized recipes for mixtures that typically contain DMSO, glycerol, and various sugar constituents. Here, we use terahertz calorimetry, Overhauser nuclear polarization, and molecular dynamics simulations to show that DMSO exhibits a robust structuring effect on water around its methyl groups, reaching a maximum at a DMSO mole fraction of X DMSO = 0.33. In contrast, glycerol exerts a smaller water-structuring effect, even at higher concentrations (Scheme 1). These results potentially suggest that the wrapped water around DMSO’s methyl group, which can be evicted upon ligand binding, may render DMSO a more…

High Resolution Image Download MS PowerPoint Slide Predicting ionic conductivity is crucial for developing efficient electrolytes for energy storage and conversion and other electrochemical applications. An accurate estimate of ionic conductivity requires understanding complex ion–ion and ion–solvent interactions governing the charge transport at the molecular level. Molecular simulations can provide key insights into the spatial and temporal behavior of electrolyte constituents. However, such insights depend on the ability of force fields to describe the underlying phenomena. In this work, molecular dynamics simulations were leveraged to delineate the impact of force field parameters on ionic conductivity predictions of potassium hydroxide (KOH) in ethylene glycol (EG). Four different force fields were used to represent the K + ion. Diffusion-based Nernst–Einstein and correlation-based Einstein approaches were implemented to estimate the ionic conductivity, and the predicted values were compared with experimental measurements. The physical aspects, including ion-aggregation, charge…

The coexistence of rigid and mobile molecules or molecular segments abounds in biomolecular assemblies. Examples include the carbohydrate-rich cell walls of plants and intrinsically disordered proteins that contain rigid β-sheet cores. In solid-state nuclear magnetic resonance (NMR) spectroscopy, dipolar polarization transfer experiments are well suited for detecting rigid components, whereas scalar-coupling experiments are well suited for detecting highly mobile components. However, few NMR methods are available to detect the segments that undergo intermediate-amplitude fast motion. Here, we introduce two NMR experiments, a two-dimensional T 2H -filtered CP-hCH correlation and a three-dimensional J-INADEQUATE CCH correlation, to observe this intermediate-amplitude motion. Both experiments involve 1 H detection under fast magic-angle spinning (MAS). By combining 1 H transverse relaxation ( T 2H ) filters with dipolar polarization transfer, we suppress the signals of both highly rigid and highly mobile species, thus revealing the signals of intermediate mobile species. 1 H detection…

High Resolution Image Download MS PowerPoint Slide The enzyme PETase from Ideonella sakaiensis ( Is PETase) strain 201-F6 can catalyze the hydrolysis of polyethylene terephthalate (PET), mainly converting it into mono(2-hydroxyethyl) terephthalic acid (MHET). In this study, we used quantum mechanics/molecular mechanics (QM/MM) simulations to explore the molecular details of the catalytic reaction mechanism of Is PETase in the formation of MHET. The QM region was described with AM1d/PhoT and M06-2 X /6-31+G(d,p) potential. QM/MM simulations unveil the complete enzymatic PET hydrolysis mechanism and identify two possible reaction pathways for acylation and deacylation steps. The barrier obtained at M06-2 X /6-31+G(d,p)/MM potential for the deacylation step corresponds to 20.4 kcal/mol, aligning with the experimental value of 18 kcal/mol. Our findings indicate that deacylation is the rate-limiting step of the process. Furthermore, per-residue interaction energy contributions revealed unfavorable contributions to the transition state of amino acids located at positions 200–230,…

The use of flavins and flavoproteins in photocatalytic, sensing, and biotechnological applications has led to a growing interest in computationally modeling the excited state electronic structure and photophysics of flavin. However, there is limited consensus regarding which computational methods are appropriate for modeling flavin’s photophysics. We compare the energies of low-lying excited states of flavin computed with time-dependent density functional theory (TD-DFT), equation of motion coupled cluster (EOM-EE-CCSD), scaled opposite-spin configuration interaction (SOS-CIS(D)), multiconfiguration pair-density functional theory (MC-PDFT), and several multi-reference perturbation theory (MR-PT2) methods. In the first part, we focus on excitation energies of the first singlet excited state (S1) of five different redox and protonation states of flavin, with the goal of finding a suitable active space for MR-PT2 calculations. In the second part, we construct two sets of one-dimensional potential energy surfaces connecting the S0 and S1 equilibrium geometries (S0–S1 path) and the S1…

Polymer informatics has attracted increasing attention as a specialized branch of material informatics. Hydrophilicity/hydrophobicity is one of the most important properties of interfaces involved in antifouling, self-cleaning, antifogging, oil/water separation, protein adsorption, and bioseparation. Establishing a quantitative structure-property relationship for the hydrophilicity/hydrophobicity of polymeric interfaces could significantly benefit from machine learning modeling. In this study, we aimed to construct machine learning models that could predict the static water contact angle (CA) as an indicator of hydrophilicity/hydrophobicity based on a data set of polymer brushes. The features of the polymer brush surfaces were numerically described using their grafted structures (thickness) and molecular descriptors derived from their chemical structures. We achieved accurate prediction and understanding of important parameters by employing appropriate molecular descriptors considering the Pearson correlation and machine learning models trained with nested cross-validation. The…

Surfactant flooding has been considered as a promising approach for chemically enhanced oil recovery (EOR). However, this technique encounters several limitations, such as high costs, environmental concerns, and reduced efficiency under high-temperature and high-salinity reservoir conditions. Recently, nanoparticles have also been proposed as an alternative for EOR due to their superior properties compared with surfactants. This research employs molecular dynamics simulations to explore the impact of modified SiO 2 nanoparticles on oil–water interfacial behaviors and the detachment of oil droplets from an oil-wet surface. The simulation results reveal that modified nanoparticles, featuring hydrophilic and hydrophobic functional groups, have slight impacts on interfacial tension reduction of the oil–water interface. Nanoparticles with varying degrees of modification exhibit distinct positions within the interface, consequently influencing the thickness of the interfacial layer. Notably, the interactions among the nanoparticles, oil molecules, and surface facilitate the formation of a…

An established method for the quantitation of the helix content in peptides using circular dichroism (CD) relies on the linear spectroscopic model. This model assumes an average value of the helix-length correction for all peptide conformers, irrespective of the length of the helical segment. Here we assess the validity of this approximation and introduce a more physically realistic ensemble-based analysis of the CD signal in which the length correction is assigned specifically to each ensemble conformer. We demonstrate that the linear model underestimates peptide helicity, with the difference depending on the ensemble composition. We developed a computer program that implements the ensemble model to estimate the peptide helicity. Using this model and the CD data set covering a broad range of helicities, we recalibrate CD baseline parameters and redetermine helix-coil parameters for the alanine-rich peptide. We show that the ensemble model leverages small differences in signal between conformers to extract more information from the experimental data, enabling the determination of…

Ionic liquids (ILs) have been used in many applications, including gas separations, electrochemistry, lubrication, and catalysis. Understanding how the different properties of ILs are related to their chemical structure and composition is crucial for these applications. Experimental investigations often provide limited insights and can be tedious in exploring a range of state points. Therefore, molecular simulations have emerged as a powerful tool that not only offers a microscopic perspective but also enables rapid screening and prediction of physical properties. The accuracy of these predictions, however, depends on the quality of the intermolecular potentials (force fields) used. The widely used classical fixed charge models, such as GAFF, OPLS, and CL&P, are popular due to their simplicity and computational efficiency. However, it has been shown that the use of integer charges with these classical models leads to sluggish dynamics. The use of scaled charge models can improve the dynamics, but these mean-field approaches are unable to account for polarization effects explicitly.…