Intrinsic Molecular Properties Research Articles

Variable PD-1 glycosylation modulates the activity of immune checkpoint inhibitors.

Monoclonal antibodies targeting the immune checkpoint PD-1 have provided significant clinical benefit across a number of solid tumors, with differences in efficacy and toxicity profiles possibly related to their intrinsic molecular properties. Here, we report that camrelizumab and cemiplimab engage PD-1 through interactions with its fucosylated glycan. Using a combination of protein and cell glycoengineering, we demonstrate that the two antibodies bind preferentially to PD-1 with core fucose at the asparagine N58 residue. We then provide evidence that the concentration of fucosylated PD-1 in the blood of non-small-cell lung cancer patients varies across different stages of disease. This study illustrates how glycoprofiling of surface receptors and related circulating forms can inform the development of differentiated antibodies that discriminate glycosylation variants and achieve enhanced selectivity, and paves the way toward the implementation of personalized therapeutic approaches.

Differentially expressed genes in orbital adipose/connective tissue of thyroid-associated orbitopathy.

Thyroid-associated orbitopathy (TAO) is a disease associated with autoimmune thyroid disorders and it can lead to proptosis, diplopia, and vision-threatening compressive optic neuropathy. To comprehensively understand the molecular mechanisms underlying orbital adipogenesis in TAO, we characterize the intrinsic molecular properties of orbital adipose/connective tissue from patients with TAO and control individuals. RNA sequencing analysis (RNA-seq) was performed to measure the gene expression of orbital adipose/connective tissues of TAO patients. Differentially expressed genes (DEGs) were detected and analyzed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and Gene Set Enrichment Analysis (GSEA). The protein-protein interaction (PPI) network was constructed using the STRING database, and hub genes were identified by the Cytoscape plug-in, cytoHubba. We validated several top DEGs through quantitative real-time polymerase chain reaction (qRT-PCR). We identified 183 DEGs in adipose tissue between TAO patients (n=3) and control patients (n=3) through RNA sequencing, including 114 upregulated genes and 69 downregulated genes. The PPI network of these DEGs had 202 nodes and 743 edges. PCR-based validation results of orbital adipose tissue showed multiple top-ranked genes in TAO patients (n=4) are immune and inflammatory response genes compared with the control individual (n=4). They include ceruloplasmin isoform x3 (CP), alkaline tissue-nonspecific isozyme isoform x1 (ALPL), and angiotensinogen (AGT), which were overrepresented by 2.27- to 6.40-fold. Meanwhile, protein mab-21-like 1 (MAB21L1), phosphoinositide 3-kinase gamma-subunit (PIK3C2G), and clavesin-2 (CLVS2) decreased by 2.6% to 32.8%. R-spondin 1 (RSPO1), which is related to oogonia differentiation and developmental angiogenesis, was significantly downregulated in the orbital muscle tissues of patients with TAO compared with the control groups (P=0.024). Our results suggest that there are genetic differences in orbital adipose-connective tissues derived from TAO patients. The upregulation of the inflammatory response in orbital fat of TAO may be consistent with the clinical phenotype like eyelid edema, exophthalmos, and excess tearing. Downregulation of MAB21L1, PIK3C2G, and CLVS2 in TAO tissue demonstrates dysregulation of differentiation, oxidative stress, and developmental pathways.

Design Principles for Balancing Lipophilicity and Permeability in beyond Rule of 5 Space.

An ab initio conformational analysis of oral beyond Rule of 5 (bRo5) drugs was complemented with measured permeability and logP(octanol) to derive design principles conferring oral bioavailability. 3D polar surface area (PSA) thresholds for oral bRo5 drugs coincided with those reported for Ro5 space. The majority of oral bRo5 drugs exceeded the Ro5 logP threshold of 5, reflecting a bias for permeability. Above 500 Da molecular weight (MW), oral drugs and highly permeable Novartis compounds occupy a narrow polarity range (topological or TPSA/MW) of 0.1-0.3 Å2 /Da, whose upper half coincides with the lower 90 percentiles of the Novartis logP set. This TPSA/MW range and 3D PSA below 100 Å2 define the "Rule of ~1 /₅" for balancing lipophilicity and permeability. Neutral TPSA, defined as TPSA minus 3D PSA occurs independent of conformation, intramolecular hydrogen bonds (IMHB) and MW, suggesting it is an intrinsic molecular property. Neutral TPSA increased in the lead optimization (LO) campaigns of three first in class de novo designed bRo5 drugs and may be a useful design parameter in bRo5 space.

Adsorption performance of the functional COFs for removal of bisphenol A: Molecular dynamic simulations

The inherent structural features of the covalent organic frameworks (COFs) play a crucial role in determining their adsorption performances for bisphenol A (BPA). The computational methods were advantageous in unraveling intrinsic molecular properties about their performances. Herein, some COFs with different functional groups (–COOH, –NH2, –NO2 and –CF3) were designed to demonstrate the efficacy of the functional COFs for adsorbed BPA in gas phase and aqueous solution. The density functional theory (DFT) and Grand Canonical Monte Carlo (GCMC) methods were used to analyze the interaction energy between COFs and BPA, structure properties, and adsorption performances etc.. The results indicated that the addition of strong electronegative functional groups in COFs increased these COFs’ isosteric heat of adsorption (Qst) (TpBD-(COOH)2 > TpBD-(CF3)2 > TpBD-(NH2)2 > TpBD-(NO2)2 > TpBD) for gas phase BPA, but their introduction also reduced the pore size of COFs (TpBD > TpBD-(COOH)2 > TpBD-(NH2)2 > TpBD-(CF3)2 > TpBD-(NO2)2). However, these functional COFs demonstrated the stronger the adsorption capacity for gas phase BPA (At 298 K and 1 bar, the BPA uptake of TpBD-(COOH)2, TpBD-(NH2)2, TpBD, TpBD-(NO2)2 and TpBD-(CF3)2 was 242.52, 232.43, 219.31, 206.64 and 197.73 mg/g, respectively.). The amount of BPA adsorbed by functional COFs was the result of the synergistic effect of the electronegativity of functional groups and the pore size. Molecular dynamic (MD) simulation performed the same phenomenon for BPA in aqueous solution. In addition, the higher temperature will decrease the adsorption amount of BPA by COF, but increase its desorption ability.

Migration behavior of water molecules and chloride ions at the nanopore scale based on molecular properties under temperature effect

The durability of cement-based materials is closely related to the transmission characteristics of water and chloride ions in the pores of calcium silicate hydrate (C-S-H) gel, especially in the climate conditions with significant temperature difference. The local structure and transport process of water molecules and chloride ions in gel pores are affected by interfacial effects. The unsaturated transport model of sodium chloride solution in C-S-H gel pores is established on the molecular scale, under different temperature and pore size conditions. Divide the regions in the C-S-H gel pore model into internal adsorption zone, external adsorption zone, and free zone. Taking into account the intrinsic mechanisms and molecular properties of water molecules and ions during transport in the C-S-H gel pores, the local structures and dynamic properties of water molecules and ions in the gel pores are quantitatively described. The electrical double layer and the double-layer water film overlap in the 1.5 nm gel pore, the water molecule and the chloride ion are closely arranged. Thus the diffusion coefficient is far lower than others, and is rarely affected by temperature. Considering the changes in the molecule properties of water and ion in different zones in molecular simulation results, a theoretical model of nanopore water and ion migration was established, revealing the migration behavior of water and ions. The results indicate that the steady-state diffusion fluxes of water and chloride ions are positively correlated with the effects of temperature and pore size, and the increasing amplitude of their diffusion fluxes is characterised by a similar phenomenon with that. This research provides a theoretical basis for the mechanism and durability of cement-based materials corroded by water and chloride ions in marine environments.

Label-Free Biosensor

Label-free biosensors have become an indispensable tool for analyzing intrinsic molecular properties, such as mass, and quantifying molecular interactions without interference from labels, which is critical for the screening of drugs, detecting disease biomarkers, and understanding biological processes at the molecular level [...].

Diserinol Isophthalamide: A Novel Reagent for Complexation with Biomolecular Anions in Electrospray Ionization Mass Spectrometry

Transferring biomolecules from solution to vacuum facilitates a detailed analysis of molecular structure and dynamics by isolating molecules of interest from a complex environment. However, inherent in the ion desolvation process is the loss of solvent hydrogen bonding partners, which are critical for the stability of a condensed-phase structure. Thus, transfer of ions to vacuum can favor structural rearrangement, especially near solvent-accessible charge sites, which tend to adopt intramolecular hydrogen bonding motifs in the absence of solvent. Complexation of monoalkylammonium moieties (e.g., lysine side chains) with crown ethers such as 18-crown-6 can disfavor structural rearrangement of protonated sites, but no equivalent ligand has been investigated for deprotonated groups. Herein we describe diserinol isophthalamide (DIP), a novel reagent for the gas-phase complexation of anionic moieties within biomolecules. Complexation is observed to the C-terminus or side chains of the small model peptides GD, GE, GG, DF-OMe, VYV, YGGFL, and EYMPME in electrospray ionization mass spectrometry (ESI-MS) studies. In addition, complexation is observed with the phosphate and carboxylate moieities of phosphoserine and phosphotyrosine. DIP performs favorably in comparison to an existing anion recognition reagent, 1,1'-(1,2-phenylene)bis(3-phenylurea), that exhibits moderate carboxylate binding in organic solvent. This improved performance in ESI-MS experiments is attributed to reduced steric constraints to complexation with carboxylate groups of larger molecules. Overall, diserinol isophthalamide is an effective complexation reagent that can be applied in future work to study retention of solution-phase structure, investigate intrinsic molecular properties, and examine solvation effects.

Characterization of the human FASTKD4 post-transcriptional regulator.

Mitochondria are multifunctional organelles responsible for vital biological processes such as energy production and programmed cell death. Mitochondrial plasticity and homeostasis are largely orchestrated by nucleic acid binding proteins tasked with regulating the mitochondrial genome, transcriptome, and proteome. Tight control of mitochondrial RNA processing events is especially important since aberrant mitochondrial RNA causes a variety of pathologies including cancer. The FASTK protein family are an emerging class of mitochondrial post-transcriptional regulators linked to diverse mitochondrial RNA processing events including RNA maturation, modification, and turnover. The FASTKD4 member is functionally linked to RNA maturation at non-canonical junctions, an important RNA processing event that liberates select RNA transcripts from its polycistronic RNA precursor. Despite its central role in RNA maturation and mitochondrial activity, FASTKD4 function and regulation remains unclear. This knowledge gap is largely due to the complete absence of biophysical and biochemical studies describing the molecular properties of FASTKD4. To address this hurdle, we reconstituted human FASTKD4 and launched a comprehensive structure-function program to identify its intrinsic molecular properties. We performed size exclusion chromatography to determine FASTKD4 is monomeric in solution. Using a quantitative fluorescence-based assay, we establish that FASTKD4 has a strong preference for single stranded RNA and correlated binding affinity with substrate length. Together, these data begin to elucidate the molecular principles driving FASTKD4's function in mitochondrial RNA maturation.

Properties of Gaseous Deprotonated L-Cysteine S-Sulfate Anion [cysS-SO3]-: Intramolecular H-Bond Network, Electron Affinity, Chemically Active Site, and Vibrational Fingerprints.

L-cysteine S-sulfate, Cys-SSO3H, and their derivatives play essential roles in biological chemistry and pharmaceutical synthesis, yet their intrinsic molecular properties have not been studied to date. In this contribution, the deprotonated anion [cysS-SO3]- was introduced in the gas phase by electrospray and characterized by size-selected, cryogenic, negative ion photoelectron spectroscopy. The electron affinity of the [cysS-SO3]• radical was determined to be 4.95 ± 0.10 eV. In combination with theoretical calculations, it was found that the most stable structure of [cysS-SO3]- (S1) is stabilized via three intramolecular hydrogen bonds (HBs); i.e., one O-H⋯⋯N between the -COOH and -NH2 groups, and two N-H⋯⋯O HBs between -NH2 and -SO3, in which the amino group serves as both HB acceptor and donor. In addition, a nearly iso-energetic conformer (S2) with the formation of an O-H⋯⋯N-H⋯⋯O-S chain-type binding motif competes with S1 in the source. The most reactive site of the molecule susceptible for electrophilic attacks is the linkage S atom. Theoretically predicted infrared spectra indicate that O-H and N-H stretching modes are the fingerprint region (2800 to 3600 cm-1) to distinguish different isomers. The obtained information lays out a foundation to better understand the transformation and structure-reactivity correlation of Cys-SSO3H in biologic settings.

Adsorption properties of a paracyclophane molecule on NaCl/Au surfaces: a first-principles study.

Ultrathin insulating layers are commonly applied in scanning tunneling microscope (STM) measurements on molecular systems to preserve the intrinsic properties of a sample. We examine in the present work the adsorption properties of a double-decker 3,3-paracyclophane (PCP) molecule supported on Au surfaces with thin NaCl monolayers (MLs) as the decoupling spacer by using first-principles calculations. The interactions between the adsorbed molecule and the substrate were analyzed in terms of the adsorption energy, dispersion interactions, charge transfer, and molecular structure changes. The simulation results show that the presence of NaCl can significantly reduce the adsorption energy as well as the charge transfer between the molecule and the substrate. Detailed analysis of the differential charge density and partial charge density of states indicates that three MLs of NaCl are sufficient to decouple the molecule from the Au substrate with no significant changes in the adsorption properties of the PCP with the further increase of the thickness of the NaCl spacer. These results could be helpful for the application of the interesting double-decker molecules as functional single-molecule devices where the intrinsic molecular properties need to be preserved.

Sub-Nanosecond Dynamics of Pathologically Relevant Bio-Macromolecules Observed by Incoherent Neutron Scattering.

Incoherent neutron scattering (iNS) is one of the most powerful techniques to study the dynamical behavior of bio-macromolecules such as proteins and lipid molecules or whole cells. This technique has widely been used to elucidate the fundamental aspects of molecular motions that manifest in the bio-macromolecules in relation to their intrinsic molecular properties and biological functions. Furthermore, in the last decade, iNS studies focusing on a possible relationship between molecular dynamics and biological malfunctions, i.e., human diseases and disorders, have gained importance. In this review, we summarize recent iNS studies on pathologically relevant proteins and lipids and discuss how the findings are of importance to elucidate the molecular mechanisms of human diseases and disorders that each study targets. Since some diseases such as amyloidosis have become more relevant in the aging society, research in this field will continue to develop further and be more important in the current increasing trend for longevity worldwide.

Molecular properties and tautomeric equilibria of isolated flavins.

Flavins are employed as redox cofactors and chromophores in a plethora of flavoenzymes. Their versatility is an outcome of intrinsic molecular properties of the isoalloxazine ring modulated by the protein scaffold and surrounding solvent. Thus, an investigation of isolated flavins with high-level electronic-structure methods and with error assessment of the calculated properties will contribute to building better models of flavin reactivity. Here, we benchmarked ground-state properties such as electron affinity, gas-phase basicity, dipole moment, torsion energy, and tautomer stability for lumiflavins in all biologically relevant oxidation and charge states. Overall, multiconfigurational effects are small and chemical accuracy is achieved by coupled-cluster treatments of energetic properties. Augmented basis sets and extrapolations to the complete basis-set limit are necessary for consistent agreement with experimental energetics. Among DFT functionals tested, M06-2X shows the best performance for most properties, except gas-phase basicity, in which M06 and CAM-B3LYP perform better. Moreover, dipole moments of radical flavins show large deviations for all functionals studied. Tautomers with noncanonical protonation states are significantly populated at normal temperatures, adding to the complexity of modeling flavins. These results will guide future computational studies of flavoproteins and flavin chemistry by indicating the limitations of electronic-structure methodologies and the contributions of multiple tautomeric states.

Photoelectron Spectroscopy of OH--Anion-Water Clusters Generated by Ultrasonic Nebulizer.

Investigating molecules in the gas phase is the only way to discover their intrinsic molecular properties; however, it is challenging to produce the gaseous phase of large-molecule chemicals. Thermal evaporation is typically used to convert molecules into gases, but it is still challenging to study ionic molecules in solutions in the gas phase. Electrospray ionization is one of the best methods to generate molecules in the gas phase, and it is uniquely capable of studying large biomolecules, including proteins. However, the molecular temperature required to study the spectroscopic properties of the molecules is very high. In this study, we developed a new, simple evaporation method using an ultrasonic nebulizer to obtain gas-phase molecules. Using this new equipment, we observed OH− anions and their water clusters in the gas phase and obtained their photoelectron spectra. We observed that the vertical electron-detachment energy (VDE) of OH− was 1.90 ± 0.05 eV and the VDEs of its water clusters and OH− (H2O)n (n = 1–2) decreased to 1.50 ± 0.05 eV (n = 1) and 1.30 ± 0.05 eV (n = 2), respectively.

Pathological cardiolipin-promoted membrane hemifusion stiffens pulmonary surfactant membranes

Lower tract respiratory diseases such as pneumonia are pervasive, affecting millions of people every year. The stability of the air/water interface in alveoli and the mechanical performance during the breathing cycle are regulated by the structural and elastic properties of pulmonary surfactant membranes (PSMs). Respiratory dysfunctions and pathologies often result in, or are caused by, impairment of the PSMs. However, a gap remains between our knowledge of the etiology of lung diseases and the fundamental properties of PSMs. For example, bacterial pneumonia in humans and mice has been associated with aberrant levels of cardiolipin, a mitochondrial-specific, highly unsaturated 4-tailed anionic phospholipid, in lung fluid, which likely disrupts the structural and mechanical integrity of PSMs. Specifically, cardiolipin is expected to significantly alter PSM elasticity due to its intrinsic molecular properties favoring membrane folding away from a flat configuration. In this paper, we investigate the structural and mechanical properties of the lipidic components of PSMs using lipid-based models as well as bovine extracts affected by the addition of pathological cardiolipin levels. Specifically, using a combination of optical and atomic force microscopy with a surface force apparatus, we demonstrate that cardiolipin strongly promotes hemifusion of PSMs and that these local membrane contacts propagate at larger scales, resulting in global stiffening of lung membranes.

Effects of the Polarity and Bulkiness of End-Functionalized Side Chains on the Charge Transport of Dicyanovinyl-End-Capped Diketopyrrolopyrrole-Based n-Type Small Molecules.

When designing organic semiconductors, side-chain engineering is as important as modifying the conjugated backbone, which has a significant impact on molecular ordering, morphology, and thus electronic device performance. We have developed three dicyanovinyl-end-capped donor-acceptor diketopyrrolopyrrole-based n-type small molecules (C2C9CN, SiC4CN, and EH4PCN) bearing an identical length of alkyl spacer yet different end-functionalized side chains (i.e., alkyl-, siloxane-, and phosphonate-end pendants). The effects of the end-functionalized side chains on the intrinsic molecular properties, microstructure, and charge transport of the small-molecule series were investigated. In comparison with the alkyl-end side chains, incorporating siloxane-end side chains into the backbone facilitates 2D edge-on oriented high intergrain connectivity/crystallinity and compatibility with the substrate surface, whereas the phosphonate-end analogues have an adverse effect on the film-forming quality due to high polarity. Thereby, an organic field-effect transistor fabricated by SiC4CN shows the best electron mobility up to 1.59 × 10-1 cm2 V-1 s-1 along with a high current on/off ratio >105. This study contributes to our understanding of the role of the end-functionalized side chains (e.g., the effects of polarity and bulkiness of the end groups) for the development of high-performance semiconductors.

Toward Low‐Temperature Lithium Batteries: Advances and Prospects of Unconventional Electrolytes

Lithium batteries have been widely used in various fields such as portable electronic devices, electric vehicles, and grid storages devices. However, the low temperature‐tolerant performances (−70 to 0 °C) of lithium batteries are still mainly hampered by low ionic conductivity of bulk electrolyte and interfacial issues. In general, there are four threats in developing low‐temperature lithium batteries when using traditional carbonate‐based electrolytes: 1) low ionic conductivity of bulk electrolyte, 2) increased resistance of solid electrolyte interphase (SEI), 3) sluggish kinetics of charge transfer, 4) slow Li diffusion throughout bulk electrodes. Meanwhile, conventional electrolytes have been close to the upper limit of optimum low‐temperature performance owing to their intrinsic molecular structural properties. As a result, it is urgent to design unconventional electrolytes with lower melting point and higher ionic conductivity. Herein, the recent key advances in regard to unconventional electrolytes including fluorinated ester, ethyl acetate, gamma‐butyrolactone, liquefied gas, ether, plastic crystal, and aqueous electrolytes are overviewed. Solvation structure modification and SEI optimization of unconventional electrolytes for low‐temperature lithium batteries are focused. Finally, aiming at the deficiencies in current understanding, the inherent limitations and envision the future prospects of low‐temperature lithium batteries are explored.

Mn(III) complexes with nitro-substituted ligands—Spin states with a twist

Structural, magnetic, and computational data on two new Mn(III) complex cations in lattices with five different counterions and varying levels of solvation are compared to investigate the influence of the position of the electron-withdrawing ligand nitro-substituent on the thermal spin crossover profile. The [MnL1]+ (a) and [MnL2]+ (b) complex cations were prepared by complexation of Mn(III) to the Schiff base chelates formed from condensation of 3-nitrosalicylaldehyde or 5-nitrosalicylaldehyde, respectively, with 1,2-bis(3-aminopropylamino)ethane and were crystallized with NO3−, (1a/b), ClO4−, (2a/b), PF6−, (3a/b), CF3SO3− (4a/b), and BPh4− (5a/b) counterions. Magnetostructural analysis reveals a minor trend in the spin state preference depending on the position of the nitro substituent where the orientation is dependent on crystal packing. Compounds using the 3-NO2-sal2-323 ligand, H2L1, where the nitro group is bent out-of-plane to the benzene ring of the Schiff base, tend to stabilize the triplet state, S = 1, while those with the 5-NO2-sal2-323 Schiff base, H2L2, where the nitro group is almost perfectly aligned in-plane with the benzene ring, mostly stabilize the spin-quintet form, S = 2. Density functional theory calculations correctly describe the energetics of intermediate spin/high spin transitions in the complexes. The intrinsic molecular magnetic properties are only marginally dependent on the position of the nitro groups; the out-of-plane orientation for the 3-NO2 is stabilized by an intramolecular hydrogen bonding interaction between the nitro group and the equatorial sal ligand. This demonstrates that the control of magnetic behavior in the solid state is mainly a cooperative effect from the size and distribution of counterions, crystal packing, and intermolecular interactions. Three potential structural phase transitions were identified, in complexes 3a, 4a, and 5a · 2MeCN including one which is not coupled to a spin state change. Finally, a break in the pattern of Jahn-Teller distortion typical for [Mn(R-Sal2-323)]+ complexes was observed in two of the complexes with the 5-NO2 ligand, where elongation of the Mn–O bond lengths on warming replaced the usual pattern of elongation of only Mn–N distances.

Oxygen vacancies modulation Mn3O4 nanozyme with enhanced oxidase-mimicking performance for l-cysteine detection

Mn3O4 nanomaterials exhibit intrinsic molecular oxygen activation properties in biomimetic and environmental catalysis. Modulating the oxygen vacancies (OVs) and identifying the oxygen activation mechanism of Mn3O4 nanomaterials are vital for designing high-performance nanozymes. Herein, the synthesized OV-Mn3O4 Nanoflowers (NFs) possesses different OVs concentrations by regulating oxygen partial pressure. The oxidase-mimicking OV-Mn3O4 NFs showed high catalytic reaction efficiency (kcat/Km) of 1.88 × 10−8 s−1 μM−1, 26.86-fold higher than Mn3O4 with poor-OVs (7.00 × 10-10 s-1 μM-1). The changes of substrates absorption, reactive oxygen species (ROS), and Mn2+/Mn3+/Mn4+ contents are attempted to illustrate clearly with the participation of OVs. Modulation OVs of Mn3O4 nanozymes can enhance the oxygen storage capacity and increase Mn species with lower valence states, which can generate abundant and multifarious ROS for the oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB) substrates. Besides, l-cysteine (l-Cys) is a pivotal amino acid for antiaging and reducing melanin. Colorimetric detection for l-Cys was established based on the enhanced oxidase-like properties of OV-Mn3O4. Compared with Mn3O4 NFs, OV-Mn3O4 NFs are exhibited more sensitive limit of detection (1.31 μM versus 5.69 μM, S/N = 3). Overall, the in-depth mechanism understanding of OVs can provide new perspective to rational design nanozymes and detection sensor with satisfactory property.

Reaction coordinates by nonlinear dimensionality reduction

Deriving reaction coordinates for the characterization of chemical reactions has long been a demanding task. In our previous work [ACS Cent. Sci. 3, 407 (2017)], the reaction coordinate of a (retro-) Claisen rearrangement in aqueous solution optimized through a Bayesian measure, a linear combination of bond lengths formation and breakage, was judged to be optimal among all trails. Here, considering the nonlinearity of the transition state, we use isometric mapping and locally linear embedding to obtain one reaction coordinate which is composed of a few collective variables. With these methods, we find a more reasonable and powerful one-dimensional reaction coordinate, which can well describe the reaction progression. To explore the reaction mechanism, we analyze the contribution of intrinsic molecular properties and the solvent-solute interactions to the nonlinear reaction coordinate. Furthermore, another coordinate is identified to characterize the heterogeneity of reaction mechanisms.

Intrinsic molecular vibration and rigorous vibrational assignment of benzene by first-principles molecular dynamics

Vibrational assignment, which establishes the correspondence between vibrational modes and spectral frequencies, is a key step in any spectroscopic study. Due to the lack of experimental technique to directly observe the thermal vibration of atoms, the assignment is usually done by empirical trial-and-error method with considerable uncertainty. Here we demonstrate a successful study of intrinsic molecular vibration property based on first-principles molecular dynamics trajectory. A unified approach for calculating and assigning vibrational frequencies is developed and applied to solve some historical issues of benzene vibration. As a major achievement, the experimental frequencies of benzene a2g and b2u vibrations are reassigned, which breaks a deadlock in contemporary spectroscopic science and removes a cloud over the application of density-functional theory in organic chemistry. This work paves the way for the comprehensive realization of the first-principles spectroscopic research, and provides crucial clues to solve the century-old problems of Kekule resonance, π-deformation, and aromaticity.