Determining dynamic structural changes along with the functional movements in biological systems has been a significant challenge for scientists for several decades. Utilizing vibrational coupling with the aid of 2D IR probe pairs has aided in uncovering structural dynamics and functional roles of chemical moieties involved in actions such as membrane peptide folding and transport, ion and water transport, and drug-protein interactions. Both native and non-native vibrational probe pairs have been developed for infrared studies, and their efficacy has been tested in various systems. With these probe pairs, 2D IR spectroscopy captures frozen snapshots of the structural events involved in biological function through vibrational coupling and correlated spectral diffusion. In this Perspective, different treatments of vibrational coupling and coupling models will be addressed, and a review of some of the specific vibrational probe pairs used to study these coupling mechanisms is presented. Overall, the intrinsic molecular dynamics detected on these ultrafast time scales will provide an atomic level view of how chosen structures traverse reaction paths. Thus, it is important to evaluate and assess the accuracy of the different vibrational coupling models and their consistency with the prediction of different molecular structures.

A profound understanding of protein structure and mechanism requires dedicated experimental and theoretical tools to elucidate electrostatic and hydrogen bonding interactions in proteins. In this work, we employed an approach to disentangle noncovalent and hydrogen-bonding electric field changes during the reaction cascade of a multidomain protein, i.e., the phytochrome Agp2. The approach exploits the spectroscopic properties of nitrile probes commonly used as reporter groups of the vibrational Stark effect. These probes were introduced into the protein through site-specific incorporation of noncanonical amino acids resulting in four variants with different positions and orientations of the nitrile groups. All substitutions left structures and the reaction mechanism unchanged. Structural models of the dark states (Pfr) were used to evaluate the total electric field at the nitrile label and its transition dipole moment. These quantities served as an internal standard to calculate the respective properties of the photoinduced products (Lumi-F, Meta-F, and Pr) based on the relative intensities of the nitrile stretching bands. In most cases, the spectral analysis revealed two substates with a nitrile in a hydrogen-bonded or hydrophobic environment. Using frequencies and intensities, we managed to extract the noncovalent contribution of the electric field from the individual substates. This analysis resulted in profiles of the noncovalent and hydrogen-bond-related electric fields during the photoinduced reaction cascade of Agp2. These profiles, which vary significantly among the four variants due to the different positions and orientations of the nitrile probes, were discussed in the context of the molecular events along the Pfr → Pr reaction cascade.

As important as molecular electrets are for electronic materials and devices, conformational fluctuations strongly impact their macrodipoles and intrinsic properties. Herein, we employ molecular dynamics (MD) simulations with the polarizable charge equilibrium (PQEq) method to investigate the persistence length () of molecular electrets composed of anthranilamide (Aa) residues. The PQEq-MD dissipates the accepted static notions about Aa macromolecules, and represents the shortest Aa rigid segments. The classical model with a single value does not describe these oligomers. Introducing multiple values for the same macromolecule follows the observed trends and discerns the enhanced rigidity in their middle sections from the reduced stiffness at their terminal regions. Furthermore, distinctly depends on solvent polarity. The Aa oligomers maintain extended conformations in nonpolar solvents with exceeding 4 nm, while in polar media, increased conformational fluctuations reduce to about 2 nm. These characteristics set key guidelines about the utility of Aa conjugates for charge-transfer systems within organic electronics and energy engineering.

Two-dimensional (2D) nanomaterials hold significant promise for reducing energy consumption in water desalination. This study investigates the influence of pore size and shape on the slip behavior of saline water at the interface of two promising 2D nanomaterials: hexagonal boron nitride (hBN) and molybdenum disulfide (MoS). Slip length, a key parameter governing fluid flow at the nanoscale, is highly dependent on interfacial properties. Here, we explore how the pore characteristics in these 2D nanomaterials can impact slip length, aiming to gain a fundamental understanding of the role of pore size and shape in optimizing desalination efficiency. We performed quantum mechanical calculations to compute the partial atomic charges on atoms in hBN and MoS containing pores. Our DFT calculations reveal a spatially varying charge distribution on these 2D nanomaterials with pores, which we then incorporate into molecular dynamic simulations to elucidate their influence on the 2D nanomaterial-water interface. Our results reveal a significant impact of pore size on friction for nanomaterials containing hexagonal pores, while pore size had no effect on nanomaterials containing triangular pores. Moreover, friction increases with pores in both materials. This research contributes to the development of efficient and energy-saving desalination technologies through the manipulation of interfacial properties in 2D nanomaterials.

Quantum-chemical fragmentation methods offer an attractive approach for the accurate calculation of protein-ligand interaction energies. While the molecular fractionation with conjugate caps (MFCC) scheme offers a rather straightforward approach for this purpose, its accuracy is often not sufficient. Here, we upgrade the MFCC scheme for the calculation of protein-ligand interactions by including many-body contributions. The resulting fragmentation scheme is an extension of our previously developed MFCC-MBE(2) scheme [ , 44, 1634-1644]. For a diverse test set of protein-ligand complexes, we demonstrate that by upgrading the MFCC scheme with many-body contributions, the error in protein-ligand interaction energies can be reduced significantly, and one generally achieves errors below 20 kJ/mol. Our scheme allows for systematically reducing these errors by including higher-order many-body contributions. As it combines the use of single amino acid fragments with high accuracy, our scheme provides an ideal starting point for the parametrization of accurate machine learning potentials for proteins and protein-ligand interactions.

Kinesin-1 is a crucial motor protein that drives the microtubule-based movement of organelles, vital for cellular function and health. Mostly studied at pH 6.9, it moves at approximately 800 nm/s, covers about 1 μm before detaching, and hydrolyzes one ATP per 8 nm step. Given that cellular pH is dynamic and alterations in pH have significant implications for disease, understanding how kinesin-1 functions across different pH levels is crucial. To explore this, we executed single-molecule motility assays paired with precise optical trapping techniques over a pH range of 5.5-9.8. Our results show a consistent positive relationship between increasing pH and the enhanced detachment (off rate) and speed of kinesin-1. Measurements of the nucleotide-dependent off rate show that kinesin-1 exhibits the highest rate of ATPase activity at alkaline pH, while it demonstrates the optimal number of ATP turnover and cargo translocation efficiency at the acidic pH. Physiological pH of 6.9 optimally balances the biophysical activity of kinesin-1, potentially allowing it to function effectively across a range of pH levels. These insights emphasize the crucial role of pH homeostasis in cellular function, highlighting its importance for the precise regulation of motor proteins and efficient intracellular transport.

Metal ions play important roles in chemistry, biochemistry, and material sciences. Accurately modeling ion solvation is crucial for simulating ion-containing systems. There are different models for ion solvation in computational chemistry, such as the explicit model, continuum model, and discrete-continuum model. Compared to the explicit model and continuum model, the discrete-continuum model of solvation is a hybrid solvation model in which the first solvation shell is described explicitly, and the remainder of the bulk liquid is characterized by a continuum model, which provides an excellent balance between accuracy and computational costs. This work serves as a systematic benchmark of the discrete-continuum model for the solvation of cations with +2, +3, and +4 charges. The calculated hydration free energies (HFEs) of ions were compared to those obtained by the SMD continuum model alone and the available experimental data. The discrete-continuum model showed improved performance over the continuum model alone via a smaller overall error and more consistent performance. Experimentally observed trends, such as the Irving-Williams series, are generally reproduced. In contrast, greater overall error was obtained for Ln ions, and the HFE trend along the Ln series was more difficult to reproduce, indicating these ions are challenging to model by the discrete-continuum model and continuum model. Overall, the discrete-continuum model is recommended to calculate the HFEs of cations when experimental data are not available.

Cyclometalated iridium(III) complexes are increasingly being developed for application in G-quadruplex (GQ) nucleic acid biosensors. We monitored the interactions of a GQ structure with an iridium(III) complex by nuclear magnetic resonance (NMR) titrations and subsequently compared the binding site inferred from NMR with binding positions modeled by molecular docking and molecular dynamics simulations. When titrated into a solution of G-quadruplex , compound ), [Ir(ppy)(pizp)](PF), where ppy is 2-phenylpyridine and pizp is 2-phenylimidazole[4,5f][1,10]phenanthroline, had the greatest impact on the hydrogen chemical shifts of G5, G8, G9, G13, and G17 residues of , indicating end-stacking at the 5' tetrad. In blind cross-docking studies with Autodock 4, end-stacking at the 5' tetrad was found as the lowest energy binding position. AMBER molecular dynamics simulations resulted in a refined binding position at the 5' tetrad with improved pi stacking. For this model system, , molecular docking and molecular dynamics simulations are tools that are able to predict the experimentally determined binding position.

In myocilin-associated glaucoma, pathogenic missense mutations accumulate mainly in the olfactomedin domain (mOLF) of myocilin. This makes the protein susceptible to aggregation, where mOLF-mOLF dimerization is possibly an initial stage. Nevertheless, there are no molecular level studies that have probed the nature of interactions occurring between two mOLF domains and the key characteristics of the resulting dimer complex. In this work, we used AlphaFold2 to obtain an I477N mutant mOLF structure with high quality followed by a stable I477N mOLF-mOLF homodimer model using molecular docking combined with molecular dynamics simulations. Moreover, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) methods coupled with per-residue energy decomposition studies are carried out to identify the key residues involved in the binding interaction. Based on these results, we provide insights into the molecular level understanding of the intermolecular interaction between two mOLF domains in an I477N homodimer. Hydrogen bonds, salt bridges, and favorable van der Waals interactions are observed in the binding interface of the homodimer. Additionally, our results suggest that I477N mutant mOLF aggregation could be a multistep process, beginning with an initial mOLF-mOLF dimerization mainly mediated by residues such as Asp395 and Arg681. Also, the peptides P1 (residues 326-337) and P3 (residues 426-442) of the mOLF domain, previously identified as pertinent for myocilin aggregation, could potentially contribute to a subsequent stage of myocilin aggregation, the first step being mOLF-mOLF dimerization.

In nature and many technological applications, aqueous solutions are in contact with patterned surfaces, which are dynamic over time scales spanning from ps to μs. For instance, in biology, exposed polar and apolar residues of biomolecules form a pattern, which fluctuates in time due to side chain and conformational motions. At metal/and oxide/water interfaces, the pattern is formed by surface topmost atoms, and fluctuations are due to, e.g., local surface polarization and rearrangements in the adsorbed water layer. All these dynamics have the potential to influence key processes such as wetting, energy relaxation, and biological function. Yet, their impact on the water H-bond network remains often elusive. Here, we leverage molecular dynamics to address this fundamental question at a self-assembled monolayer (SAM)/water interface, where ns dynamics is induced by frustrating SAM-water interactions via methylation of the terminal -OH groups of poly(ethylene glycol) (PEG) chains. We find that surface dynamics couples to the water H-bond network, inducing a response on the same ns time scale. This leads to time fluctuations of local wetting, oscillating from hydrophobic to hydrophilic environments. Our results suggest that rather than average properties, it is the local─ both in time and space─ solvation that determines the chemical-physical properties of dynamically patterned surfaces in water.

The kinetics of homogeneous crystal nucleation and the stability of nuclei were analyzed for a random butylene succinate/butylene adipate copolymer (PBSA), employing Tammann's two-stage crystal nuclei development method, with a systematic variation of the condition of nuclei transfer from the nucleation to the growth stage. Nuclei formation is fastest at around 0 °C, which is about 50 K higher than the glass transition temperature and begins after only a few seconds. Due to the high nuclei number, spherulitic growth of lamellae is suppressed. In contrast, numerous μm-sized birefringent objects are detected after melt-crystallization at high supercooling, which, at the nanometer-scale, appear composed of short lamellae with a thickness of a few nanometers only. Regarding the stability of nuclei generated at -30 °C for 100 s, it was found that the largest nuclei of the size-distribution survive temperature jumps of close to 80 K above their formation temperature. The critical transfer-heating rate to suppress the reorganization of isothermally formed nuclei as well as the formation of additional nuclei during heating increases with the growth temperature at temperatures lower than the maximum of the crystallization rate. This observation highlights the importance of careful selection of the transfer-heating rate and nuclei development temperature in Tammann's experiment for evaluation of the nucleation kinetics.

This work describes the synthesis of the LiAlCl·SO solvate complex and its properties. Its composition was determined using thermogravimetric analysis, Raman spectroscopy, and UV-vis spectroscopy. The specific ionic conductivity of LiAlCl·SO is 4.7 × 10 S·cm. The dynamic viscosity is 19 cP at 25 °C, and the lithium transference number is 0.78. The melting point (+2.5 °C) and decomposition temperature (+60 °C) of LiAlCl·SO were determined by simultaneous thermogravimetric analysis and differential scanning calorimetry. The structure of the solvate complex LiAlCl·SO has been studied using a molecular dynamics method. A lithium cation is coordinated by one atom of Cl of the anion AlCl and one oxygen atom of SO. The coordination number of lithium ions of LiAlCl·SO is 4. The lithium cation is coordinated by three anions of AlCl and one molecule of SO. Anion AlCl acts as a bridging ligand and binds different lithium cations.

Human carnosinases (CNs) are Xaa-His metal-ion-activated aminopeptidases that break down bioactive carnosine and other histidine-containing dipeptides. Carnosine is a bioactive peptide found in meat and prevalently used as a supplement and in functional food formulation. Nonetheless, carnosine is digested by CNs rapidly after ingestion. CNs have two isoforms (carnosinase 1 (CN1) and carnosinase 2 (CN2)), where CN1 is the main player in carnosine digestion. CNs contain a catalytic metal ion pair (Zn for CN1 and Mn for CN2) and two subpockets (S1 and S1' pockets) to accommodate a substrate. Bestatin (BES) has been reported to be active for CN2; however, its inhibition ability for CN1 has remained under debate, because the underlying mechanism remains unclear. This information is important for designing novel CN1-selective inhibitors for proliferating carnosine after ingestion. Thus, molecular dynamics (MD) simulations were performed to explore the binding mechanism of BES to both CN1 and CN2. The binding of BES-CN1 and BES-CN2 was studied in comparison. The results indicated that BES could bind both CNs with different degrees of binding affinity. BES prefers CN2 because: (1) its aryl terminus is trapped by Y197 in an S1 pocket; (ii) the BES polar backbone is firmly bound by catalytic Mn ions; and (iii) the S1' pocket can shrink to accommodate the isopropyl end of BES. In contrast, the high mobility of the aryl end and the complete loss of metal-BES interactions in CN1 cause a loose BES binding. Seemingly, polar termini were required for a good CN1 inhibitor.

The viscosity and diffusion properties of crowded protein systems were investigated with molecular dynamics simulations of SH3 mixtures with different crowders, and results were compared with experimental data. The simulations accurately reproduced experimental trends across a wide range of protein concentrations, including highly crowded environments up to 300 g/L. Notably, viscosity increased with crowding but varied little between different crowder types, while diffusion rates were significantly reduced depending on protein-protein interaction strength. Analysis using the Stokes-Einstein relation indicated that the reduction in diffusion exceeded what was expected from viscosity changes alone, with the additional slow-down attributable to transient cluster formation driven by weakly attractive interactions. Contact kinetics analysis further revealed that longer-lived interactions contributed more significantly to reduced diffusion rates than short-lived interactions. This study also highlights the accuracy of current computational methodologies for capturing the dynamics of proteins in highly concentrated solutions and provides insights into the molecular mechanisms affecting protein mobility in crowded environments.

Despite the advent of novel therapeutics, the efficient delivery of antineoplastic drugs remains a challenge. Biodegradable polymeric micelles represent a promising frontier by offering enhanced drug solubility, tumor targeting, and controlled release profiles. However, the underlying dynamics governing the drug encapsulation and solvation within these micellar structures is still vague and poorly understood. In this study, we used amphiphilic poly(γ-benzyloxy-ε-caprolactone)--poly(γ-2-[2-(2-methoxy ethoxy)ethoxy]ethoxy-ε-caprolactone) as a model copolymer with doxorubicin as a model drug and performed all-atom molecular dynamics simulations to understand the regulating mechanism of the encapsulation process. The results are in good agreement with the experimental results. In addition, we interpreted the dynamic behavior of the polymeric micelles and vital intermolecular interactions that play a key role in drug encapsulation. Our study provides a theoretical approach to obtain insights for designing and enhancing novel anticancer drug carriers for therapeutics.

The research presented in this paper focuses on the EWS-FLI1 oncoprotein, a critical factor in Ewing sarcoma, a rare and lethal cancer primarily affecting children and young adults. Through molecular dynamics and quantum mechanics analyses, the study explores the reactivity properties of six snapshots of the EWS-FLI1 oncoprotein, aiming to contribute to the development of targeted therapies. The investigation emphasizes the significance of understanding the molecular behavior of EWS-FLI1 for effective treatment development, utilizing computational methods such as density functional theory. The findings suggest that EWS-FLI1 is a compact, electrophilic protein with localized reactive sites, providing valuable insights for potential drug development and enhancing our knowledge of Ewing sarcoma for targeted treatments.

, a new structural indicator for water specially designed to be suitable for hydration and nanoconfined contexts, has been recently introduced and preliminarily applied for water in contact with self-assembled monolayers and graphene-like systems. This index enabled an accurate detection of defective high local density water molecules (called HDA-like given their structural resemblance with the high-density amorphous ice, HDA). In the present work, we shall apply this new metric to characterize protein hydration water with particular interest in protein binding sites. As a first result, we shall find that protein hydration water has a higher concentration of HDA-like molecular arrangements compared to the bulk. Significantly, we shall show that the concentration of HDA-like molecules sharply decreases beyond the first hydration layer. Finally, we shall also reveal a highly nonuniform spatial distribution of the values for the first hydration shell on the protein surface, where the higher hydrophobicity inherent to the ligand binding site will be evident from an enrichment in HDA-like molecules as compared to the population exhibited by the global protein surface.

Oxidized lipids arising from oxidative stress are associated with many serious health conditions, including cardiovascular diseases. For example, KDdiA-PC and KOdiA-PC are two oxidized phosphatidylcholines (oxPC) directly linked to atherosclerosis, which precipitate heart failure, stroke, aneurysms, and chronic kidney disease. These oxPCs are well-characterized in small particles such as low-density lipoprotein, but how their presence affects the biophysical properties of larger bilayer membranes is unclear. It is also unclear how membrane mediators, such as cholesterol, affect lipid bilayers containing these oxPCs. Here, we characterize supported lipid bilayers (SLBs) containing POPC, KDdiA-PC, or KOdiA-PC, and cholesterol. We used a quartz crystal microbalance with dissipation monitoring (QCM-D), fluorescence microscopy, and all-atom molecular dynamics (MD) to examine the formation process, biophysical properties, and specific lipid conformations in simulated bilayers. Experimentally, we show that liposomes containing either oxPC form SLBs by rupturing on contact with SiO substrates, which differs from the typical adsorption-rupture pathway observed with nonoxidized liposomes. We also show that increasing the oxPC concentration in SLBs results in thinner bilayers that contain defects. Simulations reveal that the oxidized -2 tails of KDdiA-PC and KOdiA-PC bend out of the hydrophobic membrane core into the hydrophilic headgroup region and beyond. The altered conformations of these oxPC, which are affected by cholesterol content and protonation state of the oxidized functional groups, contribute to trends of decreasing membrane thickness and increasing membrane area with increasing oxPC concentration. This combined approach provides a comprehensive view of the biophysical properties of membranes containing KDdiA-PC and KOdiA-PC at the molecular level, which is crucial to understanding the role of lipid oxidation in cardiovascular disease and related immune responses.

The adsorption layers of cupin-1.1, one of the two evolutionary conserved β-barrel domains of vicilin─the garden pea storage globulin─at the liquid-gas interface were studied by a few methods of the surface chemistry. The kinetic dependencies of the surface pressure of cupin-1.1 solutions in 8 M urea overlap in a single master curve if the surface pressure is plotted as a function of the normalized time. The analysis of the master curve allows separation of a few adsorption steps including the induction period, the regions of the diffusion-controlled and barrier-controlled adsorption kinetics, and a plateau region of slow adsorption. Another master curve can be constructed from the dependencies of the dynamic surface elasticity on surface pressure. This curve has some similarities with the corresponding results for recently studied cupin-1.1 spread layers on the surface of urea solutions and gliadin adsorption layers. There are also important distinctions with the master curve for adsorption layers of cupin-1.1 in the system without denaturants. This difference can be connected with the formation of larger and more rigid aggregates in pure water than the aggregates in urea solutions.

Under confinement, the water dielectric constant is a second-order tensor with an abnormally low out-of-plane element. In our work, we investigate the dielectric tensor of an aqueous NaCl solution confined by a quartz slit-pore. The static dielectric constant is determined from local polarization density fluctuations via molecular dynamics simulations. In a pioneering investigation, we evaluate not only the effect of salinity but also surface charge. The parallel dielectric constant decreases with salinity due to dielectric saturation. From a dynamic perspective, the relaxation of water dipoles is slower within the hydration shells of ions. An anisotropic arrangement on the quartz surface results in preferred orientations of interfacial water molecules. By embedding charge, the surface structure changes, and extra dipole fluctuations in one direction may develop anisotropy in the parallel dielectric constant at the interface. Both surface charge and salinity increase the perpendicular dielectric constant. Nevertheless, the surface charge effect is more pronounced and may even recover the bulk dielectric constant value. The electric field established by the charged surface may disturb the planar hydrogen bond network at the interface, increasing out-of-plane dipolar fluctuations. Our work advances the knowledge of confined dielectric behavior, shedding light on the key role that charged surfaces play.

While there is significant attention aimed at understanding how one-dimensional confinement and chain confirmations can impact the glass transition temperature () of polymer films, there remains a limited focus on similar effects on sub- processes, notably, structural relaxation. Using spectroscopic ellipsometry, we investigated the combined influence of confinement and molecular packing on and physical aging, i.e., the property changes that accompany structural relaxation, at select film thicknesses and aging temperatures (). We used poly(methyl methacrylate) (PMMA) films in the brush and spin-coated morphologies as model systems. We found that whether a PMMA film exhibited a decrease or increase in physical aging rate with confinement was dependent on the morphology. Notably, PMMA brushes exhibited higher physical aging rates compared to similarly thick spin-coated films at all values of . These intriguing findings reveal the strong effects of confinement and molecular packing on the structural relaxation of polymer films. Results from this study have the potential to aid in the design of thin-film materials with controllable long-term glassy-state properties.