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Molecular dynamics simulations are pivotal in elucidating the intricate properties of biological molecules. Nonetheless, the reliability of their outcomes hinges on the precision of the molecular force field utilized. In this perspective, we present a comprehensive review of the developmental trajectory of the Amber additive protein force field, delving into researchers' persistent quest for higher precision force fields and the prevailing challenges. We detail the parameterization process of the Amber protein force fields, emphasizing the specific improvements and retained features in each version compared to their predecessors. Furthermore, we discuss the challenges that current force fields encounter in balancing the interactions of protein–protein, protein–water, and water–water in molecular dynamics simulations, as well as potential solutions to overcome these issues. [ABSTRACT FROM AUTHOR]

In this work, we present a multiscale real-time approach to study the plasmonic effects of a metal nanoparticle (NP) on the electronic circular-dichroism (ECD) spectrum of a chiral molecule interacting with it. The method is based on the time-evolution of the molecule's time-dependent wavefunction, expanded in the eigenstates of a perturbed Hamiltonian. A quantum description of the molecular system is coupled to a classical representation of the NP via a continuum model. The method is applied to methyloxirane and peridinin at various distances (1, 3, and 5 nm) with respect to a gold NP surface. While no remarkable effect is observed for methyloxirane at any studied distance, an enhancement appears when the peridinin lies at 1 nm and the pulse is linearly polarized perpendicularly to the molecular axis, with the ECD signal centered at 4.1 eV increased by a factor of around 20. These results are rationalized looking at the gap between the plasmonic peak of the NP at around 2.5 eV and the molecular excitations: the smaller the gap between molecular and plasmonic excitations, the larger the plasmonic enhancement of the ECD signal. Moreover, ECD peaks are selectively enhanced due to the favorable coupling between the pulse polarization and the combined effect of electric and magnetic dipole moments. This approach allows one to go through the electronic structure and dynamics of chiral molecules for obtaining a realistic description of plasmon-mediated ECD spectra, e.g., paving the way to applications to molecules of biological relevance interacting with nanostructures of experimental interest. [ABSTRACT FROM AUTHOR]

Low-temperature plasma (LTP) is being advanced as an alternative radiation source that offers unique chemical properties demonstrated in a variety of reactive plasma species, in which electrons are the primary species derived upon plasma irradiation. We employed a simple and reliable protocol based on two-electron reduction of nitrate into nitrite ions coupled with fluorometric detection to quantify the uptakes of solvated electrons in irradiated solutions under two distinct plasma conditions of our LTP source. In addition, we explored the influence of other plasma species and the solution pH on the uptake rates. Under such conditions, the estimated uptake of solvated electrons was below 0.1 mM, suggesting that this value represents the minimum concentration of plasma electrons transferred to the solution. Quantifying plasma electrons accurately is particularly important for LTP applications that involve biological molecules, as they are susceptible to damage by low-energy electrons. [ABSTRACT FROM AUTHOR]

Traditional molecular dynamics simulation of biomolecules suffers from the conformational sampling problem. It is often difficult to produce enough valid data for post analysis such as free energy calculation and transition path construction. To improve the sampling, one practical solution is putting an adaptive bias potential on some predefined collective variables. The quality of collective variables strongly affects the sampling ability of a molecule in the simulation. In the past, collective variables were built with the sampling data at a constant temperature. This is insufficient because of the same sampling problem. In this work, we apply the standard weighted histogram analysis method to calculate the multi-ensemble averages of pairs of time-lagged features for the construction of both linear and nonlinear slow collective variables. Compared to previous single-ensemble methods, the presented method produces averages with much smaller statistical uncertainties. The generated collective variables help a peptide and a miniprotein fold to their near-native states in a short simulation time period. By using the method, enhanced sampling simulations could be more effective and productive. [ABSTRACT FROM AUTHOR]

Biomolecules inhabit a crowded living cell that is packed with high concentrations of cosolutes and macromolecules that result in restricted, confined volumes for biomolecular dynamics. To understand the impact of crowding on the biomolecular structure, the combined effects of the cosolutes (such as urea) and confinement need to be accounted for. This study involves examining these effects on the collapse equilibria of three model 32-mer polymers, which are simplified models of hydrophobic, charge-neutral, and uncharged hydrophilic polymers, using molecular dynamics simulations. The introduction of confinement promotes the collapse of all three polymers. Interestingly, addition of urea weakens the collapse of the confined hydrophobic polymer, leading to non-additive effects, whereas for the hydrophilic polymers, urea enhances the confinement effects by enhancing polymer collapse (or decreasing the polymer unfolding), thereby exhibiting an additive effect. The unfavorable dehydration energy opposes collapse in the confined hydrophobic and charge-neutral polymers under the influence of urea. However, the collapse is driven mainly by the favorable change in polymer–solvent entropy. The confined hydrophilic polymer, which tends to unfold in bulk water, is seen to have reduced unfolding in the presence of urea due to the stabilizing of the collapsed state by urea via cohesive bridging interactions. Therefore, there is a complex balance of competing factors, such as polymer chemistry and polymer–water and polymer–cosolute interactions, beyond volume exclusion effects, which determine the collapse equilibria under confinement. The results have implications to understand the altering of the free energy landscape of proteins in the confined living cell environment. [ABSTRACT FROM AUTHOR]

The unfolding of molecular complexes or biomolecules under the influence of external mechanical forces can routinely be simulated with atomistic resolution. To obtain a match of the characteristic time scales with those of experimental force spectroscopy, often coarse graining procedures are employed. Here, building on a previous study, we apply the adaptive resolution scheme (AdResS) to force probe molecular dynamics (FPMD) simulations using two model systems as examples: One system is the previously investigated calix[4]arene dimer that shows reversible one-step unfolding, and the other example is provided by a small peptide, a β-alanine octamer in methanol solvent. The mechanical unfolding of this peptide proceeds via a metastable intermediate and, therefore, represents a first step toward a complex unfolding pathway. We show that the average number of native contacts serves as a robust order parameter for the forced unfolding of this small peptide. In addition to increasing the complexity of the relevant conformational changes, we study the impact of the methodology used for coarse graining. Apart from the iterative Boltzmann inversion method, we apply an ideal gas approximation, and therefore, we replace the solvent by a non-interacting system of spherical particles. In all cases, we find excellent agreement between the results of FPMD simulations performed fully atomistically and those of the AdResS simulations also in the case of fast pulling. This holds for all details of the unfolding pathways, such as the distributions of the characteristic forces and also the sequence of hydrogen-bond opening in case of the β-alanine octamer. Therefore, the methodology is very well suited to simulate the mechanical unfolding of systems of experimental relevance. [ABSTRACT FROM AUTHOR]

The transport of molecules through biological and synthetic nanopores is governed by multiple stochastic processes that lead to noisy, fluctuating currents. Disentangling the characteristics of different noise-generating mechanisms is central to better understanding molecular transport at a fundamental level but is extremely challenging in molecular systems due to their complexity and relative experimental inaccessibility. Here, we construct a colloidal model microfluidic system for the experimental measurement of particle currents, where the governing physical properties are directly controllable and particle dynamics directly observable, unlike in the molecular case. Currents of hard spheres fluctuate due to the random arrival times of particles into the channel and the distribution of particle speeds within the channel, which results in characteristic scalings in the power spectral density. We rationalize these scalings by quantitatively comparing to a model for shot noise with a finite transit time, extended to include the distribution of particle speeds. Particle velocity distributions sensitively reflect the confining geometry, and we interpret and model these in terms of the underlying fluid flow profiles. Finally, we explore the extent to which details of these distributions govern the form of the resulting power spectral density, thereby establishing concrete links between the power spectral density and underlying mechanisms for this experimental system. This paves the way for establishing a more systematic understanding of the links between characteristics of transport fluctuations and underlying molecular mechanisms in driven systems such as nanopores. [ABSTRACT FROM AUTHOR]

The transport of particles through channels holds immense significance in physics, chemistry, and biological sciences. For instance, the motion of solutes through biological membranes is facilitated by specialized proteins that create water-filled channels. Valuable insights can be obtained by studying the transition paths of particles through a channel and gathering information on their lifetimes inside the channel as well as their exit probabilities. In a similar vein, we consider a one-dimensional model of channel-facilitated transport where a diffusive particle is subject to attractive interactions with the walls of the channel. We study the statistics of conditional and unconditional escape times in the presence of resetting—an intermittent dynamics that brings the particle back to its initial coordinate stochastically. We determine analytically the physical conditions under which such a resetting mechanism becomes beneficial for the faster escape of the particles from the channel, thus enhancing transport. Our theory has been verified with the aid of Brownian dynamics simulations for various interaction strengths and extents. The overall results presented herein highlight the scope of resetting-based strategies to be universally promising for complex transport processes of single or long molecules through biological membranes. [ABSTRACT FROM AUTHOR]

We investigate the vertical electron attachment energy (VAE) of 1-methyl-4-nitroimidazole, a model radiosensitizer, employing quantum mechanics/molecular mechanics (QM/MM) and QM/polarized continuum (QM/PCM) solvation models. We considered the solvent-excluded surface (QM/PCM-SES) and Van der Waals (QM/PCM-VDW) cavities within the PCM framework, the electrostatic embedding QM/MM (EE-QM/MM) model, and the self-consistent sequential QM/MM polarizable electrostatic embedding (scPEE-S-QM/MM) model. Due to slow VAE convergence concerning the number of QM solvent molecules, full QM calculations prove inefficient. Ensemble averages in these calculations do not align with VAEs computed for the representative solute–solvent configuration. QM/MM and QM/PCM calculations show agreement with each other for sufficiently large QM regions, although the QM/PCM-VDW model exhibits artifacts linked to the cavity. QM/MM models demonstrate good agreement between ensemble averages and VAEs calculated with the representative configuration. Notably, the VAE computed with the scPEE-S-QM/MM model achieves faster convergence concerning the number of QM water molecules compared to the EE-QM/MM model, attributed to enhanced efficiency from MM charge polarization in the scPEE-S-QM/MM approach. This emphasizes the importance of QM/classical models with accurate solute–solvent and solvent–solvent mutual polarization for obtaining converged VAEs at a reasonable computational cost. The full-QM approach is very inefficient, while the microsolvation model is inaccurate. Computational savings in QM/MM models result from electrostatic embedding and the representative configuration, with the scPEE-S-QM/MM approach emerging as an efficient tool for describing bulk-solvated anions within the QM/MM framework. Its potential extends to improving transient anion state descriptions in biomolecules and radiosensitizers, especially given the frequent employment of microsolvation models. [ABSTRACT FROM AUTHOR]

Click chemistry refers to selective reactions developed for grafting of bio(macro)molecules in their biological media. Caged click compounds have been employed to spatiotemporally control click reactions. Here, we survey the uncaging of photo-dibenzocyclooctyne-OH (photoDIBO-OH) to its click-chemistry active form DIBO-OH, with particular attention to its conversion timescale and efficiency. Ultraviolet pump–infrared probe experiments reveal a stepwise decarbonylation: first, carbon monoxide (C≡O) is released within 1.8 ps, and then, it converts, within 10 ps, to DIBO-OH. Completion of uncaging is achieved with an efficiency of ∼50%. A successful demonstration of two-photon uncaging of photoDIBO-OH at long wavelength (700 nm) confers enhanced in vivo compatibility and proceeds on the same timescale. [ABSTRACT FROM AUTHOR]

Phase separation of biomolecules can facilitate their spatiotemporally regulated self-assembly within living cells. Due to the selective yet dynamic exchange of biomolecules across condensate interfaces, condensates can function as reactive hubs by concentrating enzymatic components for faster kinetics. The principles governing this dynamic exchange between condensate phases, however, are poorly understood. In this work, we systematically investigate the influence of client–sticker interactions on the exchange dynamics of protein molecules across condensate interfaces. We show that increasing affinity between a model protein scaffold and its client molecules causes the exchange of protein chains between the dilute and dense phases to slow down and that beyond a threshold interaction strength, this slowdown in exchange becomes substantial. Investigating the impact of interaction symmetry, we found that chain exchange dynamics are also considerably slower when client molecules interact equally with different sticky residues in the protein. The slowdown of exchange is due to a sequestration effect, by which there are fewer unbound stickers available at the interface to which dilute phase chains may attach. These findings highlight the fundamental connection between client–scaffold interaction networks and condensate exchange dynamics. [ABSTRACT FROM AUTHOR]

The projector augmented wave (PAW) method of Blöchl linearly maps smooth pseudo wavefunctions to the highly oscillatory all-electron DFT orbitals. Compared to norm-conserving pseudopotentials (NCPP), PAW has the advantage of lower kinetic energy cutoffs and larger grid spacing at the cost of having to solve for non-orthogonal wavefunctions. We earlier developed orthogonal PAW (OPAW) to allow the use of PAW when orthogonal wavefunctions are required. In OPAW, the pseudo wavefunctions are transformed through the efficient application of powers of the PAW overlap operator with essentially no extra cost compared to NCPP methods. Previously, we applied OPAW to DFT. Here, we take the first step to make OPAW viable for post-DFT methods by implementing it in real-time time-dependent (TD) DFT. Using fourth-order Runge–Kutta for the time-propagation, we compare calculations of absorption spectra for various organic and biological molecules and show that very large grid spacings are sufficient, 0.6–0.7 bohr in OPAW-TDDFT rather than the 0.4–0.5 bohr used in traditional NCPP-TDDFT calculations. This reduces the memory and propagation costs by around a factor of 3. Our method would be directly applicable to any post-DFT methods that require time-dependent propagations such as the GW approximation and the Bethe–Salpeter equation. [ABSTRACT FROM AUTHOR]

In the folded state, biomolecules exchange between multiple conformational states crucial for their function. However, most structural models derived from experiments and computational predictions only encode a single state. To represent biomolecules accurately, we must move towards modeling and predicting structural ensembles. Information about structural ensembles exists within experimental data from X-ray crystallography and cryo-electron microscopy. Although new tools are available to detect conformational and compositional heterogeneity within these ensembles, the legacy PDB data structure does not robustly encapsulate this complexity. We propose modifications to the macromolecular crystallographic information file (mmCIF) to improve the representation and interrelation of conformational and compositional heterogeneity. These modifications will enable the capture of macromolecular ensembles in a human and machine-interpretable way, potentially catalyzing breakthroughs for ensemble-function predictions, analogous to the achievements of AlphaFold with single-structure prediction.

Polymer models describing the statistics of biomolecules under confinement have applications to a wide range of single-molecule experimental techniques and give insight into biologically relevant processes in vivo. In this paper, we determine the transverse position and bending correlation functions for a wormlike chain confined within slits and cylinders (with one and two confined dimensions, respectively) using a mean-field approach that enforces rigid constraints on average. We show the theoretical predictions accurately capture the statistics of a wormlike chain from Monte Carlo simulations in both confining geometries for both weak and strong confinement. We also show that the longitudinal correlation function is accurately computed for a chain confined to a slit and leverages the accuracy of the model to suggest an experimental technique to infer the (often unobservable) transverse statistics from the (directly observable) longitudinal end-to-end distance. [ABSTRACT FROM AUTHOR]

We report on our progress towards the synthesis of the exotic, delicate, and tense polyketidic macrolactam of incednine. This work constitutes a significant advancement towards the total synthesis of a family of molecules of biological and medicinal interest. Some of the key features of this synthesis required evolutions from the initially designed strategy, leading to the use of a Horner–Wadsworth–Emmons olefination to build the C2–C9 tetraene. For this purpose, a polyfunctionalized phosphonate was used that was obtained through an unprecedented Pd-catalyzed cross-coupling involving the zinc salt of diethyl methylphosphonate. The resulting desired C1–C15 fragment displays a carboxylic acid ester at C1 and a vinyl iodide at C15, both functions being ready for subsequent amide coupling with the C16–C23 fragment and final Suzuki cyclization, respectively. [ABSTRACT FROM AUTHOR]

The expulsion of protein-coupled water and protein hydration enhance and attenuate the aggregation propensity of Amyloid β(1–42), respectively, leading to different degrees of aggregation. [Display omitted] Protein hydration water is essential for protein misfolding and amyloid formation, but how it directs the course of amyloid formation has yet to be elucidated. Here, we experimentally demonstrated that femtosecond sum frequency generation vibrational spectroscopy (SFG–VS) and the femtosecond IR pump–SFG probe technique can serve as powerful tools for addressing this issue. Using amyloid β(1–42) peptide as a model, we determined the transient misfolding intermediates by probing the amide band spectral features and the local hydration water changes by measuring the ultrafast vibrational dynamics of the amide I band. For the first time, we established a correlation between the dynamic change in protein hydration water and aggregation propensity. The aggregation propensity depends on the dynamic change in the hydration water, rather than the static hydration water content of the initial protein state. Water expulsion enhances the aggregation propensity and promotes amyloid formation, while protein hydration attenuates the aggregation propensity and inhibits amyloid formation. The suppression of water expulsion and protein hydration can prevent protein aggregation and stabilize proteins. These findings contribute to a better understanding of the underlying effect of hydration water on amyloid formation and protein structural stability and provide a strategy for maintaining long–term stabilization of biomolecules. [ABSTRACT FROM AUTHOR]

Single-atom catalysts (SACs), with advantages of high catalytic activity, high stability and high selectivity, have displayed a perfect performance in electro- chemically sensing small biological molecules. However, SACs were in scare case to be employed in electroanalysis on dihydroxybenzene isomers. Hence, high- temperature pyrolysis-derived Cu-based single-atom catalyst (Cu-SAC) was obtained and then was observed to own an outstanding property on detecting dihydroxybenzene isomers. Cu-SAC exhibited a large specific surface area and highly dispersed active sites that were uniformly distributed on N-doped porous carbon characterized by XRD, SEM, TEM, HAADF-STEM, XPS and BET. The electrochemical sensor based on Cu-SAC demonstrated a wide detection range of 1–100 μM and the significant sensitivity for the simultaneous measurement of hydroquinone (HQ) and catechol (CC) under optimal conditions. The detection limits for both isomers were around 0.11 μM for HQ and 0.33 μM for CC, respectively. Additionally, this sensor was successfully utilized to identify HQ and CC in a tap water sample. [ABSTRACT FROM AUTHOR]

The 4-(4-pyridinyl)thiazole-2-thiol (HPTT) molecule with biological activities is a sulfur-containing organic ligand. Here, one new sulfur-containing coordination polymer based on HPTT and potassium thiocyanate (KSCN), namely, {[Cd(PTT)(HPTT)(SCN)}n, has been synthesized and characterized by physicochemical methods. The single-crystal X-ray diffraction analyses reveal the compound crystallizes in a monoclinic P21/n space group and features a one-dimensional line structure. The crystal structure is stabilized through intramolecular C–H···N and C–H···S hydrogen bonds and intermolecular N–H···N, C–H···π, and π⋯π interactions, generating a two-dimensional supramolecular layer structure. The interactions are also analyzed using Hirshfeld surface analysis. Moreover, the compound shows a relatively thermal stability and solid-state photoluminescence at room temperature. One new sulfur-containing coordination polymer based on 4-(4-pyridinyl)thiazole-2-thiol and potassium thiocyanate has been synthesized and characterized. The single-crystal X-ray diffraction analyses reveal the compound crystallizes in a monoclinic P21/n space group and features a one-dimensional line structure. The crystal structure is stabilized by hydrogen bonds and π⋅⋅⋅π stacking interactions, generating a two-dimensional supramolecular layer structure. The interactions are also analyzed using Hirshfeld surface analysis. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Indolizine is a nitrogen‐containing heterocycle with strong aromaticity, possessing a delocalized 10π‐electron system. Based on the indolizine scaffolds, numerous molecules with biological activity and organic functional materials have been synthesized. Since 2016, over 110 papers have been published on the synthesis of indolizine scaffolds, but the reviews on synthesizing indolizine scaffolds have been incomplete and not up‐to‐date. Herein, from the perspective of the structure of indolizine with the combination of pyrrole and pyridine ring, we focus on the construction of indolizine scaffolds through the diversity of starting substrates, including pyridine derivatives (N1‐substituted pyridinium salt derivatives, C2‐substituted pyridine derivatives, N1‐ and C2‐free substituted pyridine derivatives), pyrrole derivatives and unoriginal ring substrates. Furthermore, the corresponding reaction mechanisms of synthetic methodologies are also elaborated. Therefore, this review not only paves the way for indolizine synthesis but also provides insight into exploring new reaction modes for constructing nitrogen‐containing heterocycles. Key Scientists: Indolizine was discovered by Angeli in 1890 and first prepared by Scholtz in 1912 from α‐picoline and acetic anhydride. A general approach was developed by Chichibabin in 1927, that is of practical value for the preparation of 2‐alkyl‐ or 2‐arylindolizines. The Chichibabin reaction was the ring closure of quaternary pyridinium halides. At the begining of the 21st century, Basavaiah introduced a new dimension in the Baylis‐Hillman chemistry leading to a novel facile convenient methodology for synthesis of indolizine scaffolds in one‐pot operation. In 2010, Barluenga reported Cu(I)‐catalyzed regioselective [3+2] cyclization of unsubstituted pyridines toward alkenyldiazoacetates leading to functionalized indolizine derivatives, that was the first successful example of metal‐catalyzed cyclization of a π‐deficient heterocyclic system with alkenyldiazo compounds. In 2019 and 2022, Xi and Liu exploited the methods of non‐pyridine derivatives as starting materials to synthesize indolizines, respectively. In 2022, Guo developed an environmentally benign electrooxidative approach for constructing formyl‐ and acyl‐substituted indolizines. [ABSTRACT FROM AUTHOR]

Leech therapy has been utilized in modern and traditional medicine. Leech saliva contains versatile peptides and molecules that can exert anti-microbial, anti-inflammatory, anti-coagulant, and analgesic activities on the patients. The active components and molecular mechanism of action of these components should be deciphered properly in order to generate biotechnological drug candidates by recombinant production of the leech saliva peptides. In our study, we conducted LC–MS/MS and proteomics analysis on the lyophilized leech saliva extract to determine the components of it. Moreover, this extract was tested on the in vitro-activated macrophages. The extract decreased the production of the pro-inflammatory cytokines by the activated mammalian macrophages compared to the positive control groups. These results suggest that the lyophilized leech saliva can be utilized as an anti-inflammatory biotechnological drug candidate against inflammatory and autoimmune disorders. In vitro studies will be conducted to further decipher the most active ingredients in the leech saliva. These active components will be tested on the animal models of the inflammatory and autoimmune disorders to show their drug potential. [ABSTRACT FROM AUTHOR]

Surface coatings with polyethylene glycol (PEG) polymers have often been employed to improve nanoparticles (NPs) biocompatibility and extend circulation time by reducing protein adsorption. PEGylated NPs benefit from steric hindrance and repulsion effects, which are influenced by PEG molecular weight, density, and chain conformation. However, repetitive exposure to PEG can trigger acute and chronic immunological responses as a result of the development of Immunoglobulin G anti-PEG antibodies. NPs functionalisation with glycans has become an emerging approach to increase their biocompatibility as these biomolecules are highly hydrophilic, biocompatible interact with biological receptors expressed in the body, and can be conjugated, controlling their orientation. In this study, we developed a series of gold NPs (AuNPs) coated with PEG linkers of different lengths and conjugated with mannose (Man) or sialic acid (Sia) glycans, and we carried out a detailed characterisation prior to and after exposure to biological fluids to study their behaviour and protein corona formation. Our findings show that the glycan-coated NPs exhibit stabilisation after protein interaction, with Man coatings showing the lowest protein affinity and that the glycans are biologically active and capable of binding to glycan receptors (such as Concanavalin A) despite the presence of a complex protein environment. Results indicate that glycan modification of PEGylated NPs reduces nonspecific interactions while preserving active targeting properties, underscoring their potential for therapeutic applications. [ABSTRACT FROM AUTHOR]