Trimer Complexes Research Articles

Hydrogen bonding in 2,2,2-trifluoroethanol.

2,2,2-Trifluoroethanol (TFE) is known as a membrane mimetic solvent. The IR spectrum, 1H NMR spectrum, 13C NMR spin‒lattice relaxation times (T1), and nuclear Overhauser effect (NOE) data are consistent with extensive hydrogen bonding in TFE, but do not lead to structural features of the hydrogen bonding. Hence, DFT computations were carried out. The results predict the existence of a set of H-bonded dimers and trimers. The bond lengths and dihedral angles in these complexes are obtained, together with their dissociation energies. Computations were also performed for the geometry of the two conformers of the isolated monomer. The structure of one of the dimers consists of a 7-member cyclic fragment with a free CF3CH2 side chain. One set of the trimer structures involves the OH of a third monomer H-bonding to one of the F atoms in the CF3 group of the side chain of this dimer, thereby creating three trimer isomers. A fourth trimer cluster is formed from three monomers in which three OH∙∙∙O bonds create a cyclic fragment with three CF3CH2 side chains. The high dissociation energy (with respect to three monomers) indicates the high stability of the trimer complexes. The structural features of the trimer complexes resemble the structure of a conventional liquid crystal molecule and are postulated to resemble the latter in properties and function in solution, but at a much shorter timescale because of the noncovalent bonding. This hydrogen bonding phenomenon of TFE may be related to its function as a membrane memetic solvent. Initially, IR and NMR spectroscopic methods were used. Standard procedures were followed. For the computations, a hybrid DFT method with empirical dispersion, ωB97X-D, was used. The basis set, 6-311++G**, is of triple-ζ quality, in which polarization functions and diffuse functions were added for all atoms.

Comparative Analysis of Conformational Dynamics and Systematic Characterization of Cryptic Pockets in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB.1 Spike Complexes with the ACE2 Host Receptor: Confluence of Binding and Structural Plasticity in Mediating Networks of Conserved Allosteric Sites.

In the current study, we explore coarse-grained simulations and atomistic molecular dynamics together with binding energetics scanning and cryptic pocket detection in a comparative examination of conformational landscapes and systematic characterization of allosteric binding sites in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB.1 spike full-length trimer complexes with the host receptor ACE2. Microsecond simulations, Markov state models and mutational scanning of binding energies of the SARS-CoV-2 BA.2 and BA.2.75 receptor binding domain complexes revealed the increased thermodynamic stabilization of the BA.2.75 variant and significant dynamic differences between these Omicron variants. Molecular simulations of the SARS-CoV-2 Omicron spike full-length trimer complexes with the ACE2 receptor complemented atomistic studies and enabled an in-depth analysis of mutational and binding effects on conformational dynamic and functional adaptability of the Omicron variants. Despite considerable structural similarities, Omicron variants BA.2, BA.2.75 and XBB.1 can induce unique conformational dynamic signatures and specific distributions of the conformational states. Using conformational ensembles of the SARS-CoV-2 Omicron spike trimer complexes with ACE2, we conducted a comprehensive cryptic pocket screening to examine the role of Omicron mutations and ACE2 binding on the distribution and functional mechanisms of the emerging allosteric binding sites. This analysis captured all experimentally known allosteric sites and discovered networks of inter-connected and functionally relevant allosteric sites that are governed by variant-sensitive conformational adaptability of the SARS-CoV-2 spike structures. The results detailed how ACE2 binding and Omicron mutations in the BA.2, BA.2.75 and XBB.1 spike complexes modulate the distribution of conserved and druggable allosteric pockets harboring functionally important regions. The results are significant for understanding the functional roles of druggable cryptic pockets that can be used for allostery-mediated therapeutic intervention targeting conformational states of the Omicron variants.

EPR and SQUID interrogations of Cr(III) trimer complexes in the MIL-101(Cr) and bimetallic MIL-100(Al/Cr) MOFs

Herein, electron paramagnetic resonance (EPR) spectroscopy at X- (9.4 GHz), Q- (34 GHz) and W-band (95 GHz), and superconducting quantum interference device (SQUID) measurements on antiferromagnetically coupled metal trimers in MIL-101(Cr) and MIL-100(Al_{0.8}0.8Cr_{0.2}0.2) MOFs were investigated. At low temperatures, the Cr(III) trimers exhibit a Dzyaloshinsky-Moriya (D-M) interaction, and have a total spin state S_T = 1/2T=1/2.

Abstract 5668: Using clinical utility index (CUI) to determine the optimal biological dose of a nonfucosylated anti-TIGIT antibody: A proposed alternative to maximum tolerated dose (MTD)

Abstract SEA-TGT is a human nonfucosylated monoclonal antibody (mAb) targeting the T cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) protein. TIGIT is an immunoregulatory receptor expressed on activated and memory T cells, Tregs, and NK cells. TIGIT binding to CD155 and CD112 on tumor cells drives an inhibitory signal resulting in decreased T cell functionality. TIGIT targeting has been reported to release these inhibitory signals, drive Treg depletion, augment CD8+ T cell generation, and promote anti-tumor responses. SGNTGT-001 (NCT04254107) is a phase 1 clinical trial that evaluated the safety and tolerability of SEA-TGT as monotherapy in solid tumors and lymphomas at doses ranging from 0.01 to 6 mg/kg. Because an MTD was not identified in dose escalation, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints were measured to assess biological activity and inform dose selection. The biological activity of SEA-TGT as monotherapy was compared across different dose levels using a clinical utility index (CUI), which mathematically integrated multiple clinically-meaningful PK and PD endpoints into a single readout. PD endpoints included NK and CD8+ T cell proliferation, maintenance of overall peripheral CD8+ T cell numbers, depletion of peripheral regulatory T cells, and peripheral target engagement. The PK endpoint was pharmacokinetic linearity. Surrogates of predicted tumor efficacy metrics included tumor target engagement and formation of the TIGIT:SEA-TGT:Fc receptor gamma (FcγRIIIa) trimer complexes in the tumor. An increase in the CUI score, representing an increase in biological activity, was observed during dose escalation, with an apparent plateau between the 0.3 and 6.0 mg/kg levels. Based on safety signals at 6 mg/kg and PK variability at lower doses, 1 and 3 mg/kg were of most interest for further evaluation. Both 1 and 3 mg/kg represented biologically active dose levels as they showed PK and PD activity that were within desirable ranges and had similarly high overall CUI scores relative to all doses evaluated. Dose selection for SEA-TGT was based on biological activity as assessed via PK/PD endpoints and integrated into a CUI model. Based on the totality of clinical data and the CUI results from monotherapy dose escalation from SGNTGT-001, the SEA-TGT dose of 1 mg/kg was determined to be the lowest biologically active dose with acceptable safety and tolerability. Citation Format: Gabriela Patilea-Vrana, John Harrold, Joseph A. Ware, Shaparak Lonning, Hun Lee, Lisa Brooks, Haley Neff-LaFord, William D. Hanley, Andres Forero-Torres. Using clinical utility index (CUI) to determine the optimal biological dose of a nonfucosylated anti-TIGIT antibody: A proposed alternative to maximum tolerated dose (MTD). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5668.

Abstract 846: Utilizing quantitative systems pharmacology (QSP) model to understand cytokine release syndrome (CRS) following administration of epcoritamab in DLBCL patients

Abstract Background: Epcoritamab is a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells (1). Epcoritamab’s pharmacokinetics (PK), pharmacodynamics, and safety profiles were investigated in GCT3013-01 escalation study across a wide range of doses. CRS is an adverse event of special interest for T cell engagers such as Epcoritamab. As such, step-up dosing (SUD) has been investigated in study GCT3013-01 escalation to minimize release of cytokines and mitigate severe CRS symptoms. Seventeen permutations of SUD were tested, with doses ranging from 0.004 to 60 mg. Based on observed CRS data, a SUD regimen of 0.16/0.8/48 mg was selected. The aim of the analysis was to develop a QSP model capable of predicting cytokine release which can be used to identify potential optimal SUD regimen. Method: Leveraging Epcoritamab preclinical and clinical data, we have developed a QSP platform that captures the observed tumor responses and allows for systemic predictions of biomarkers with the selected SUD regimen. A minimal physiologically based PK model was linked to submodels of T cell activation, proliferation, and cytotoxicity of target-bearing cells, to create an integrated QSP model of the DLBCL system. Epcoritamab-mediated cross-linking of target(s) and CD3 receptor to form trimer complexes drives cell trafficking and cytokine production as well as inducing death of target-bearing cells. The model described the PK, cellular effects, and observed cytokine profiles within the plasma, and simulated similar effects in lymph node(s), tumor, and other peripheral body tissue. Result: After SC administration of Epcoritamab, transient and modest elevation of selected cytokines was observed. Patients’ cytokine profiles were categorized into three different trends based on Cycle 1 data. By accounting for the interaction of receptors and ligands at the nano-scale level (time and physical size) we characterized the dose response and dynamics of T cells, B cells, IL6, and IL10 in patients enrolled in the study by using the QSP model. Conclusions: This analysis integrated underlying mechanisms to predict various systemic biomarkers dynamics including T cells, B cells, IL6 and IL10 following administration of Epcoritamab. The well-studied pathways and mechanisms allow implementation of the model in disease indications other than DLBCL.

Comprehensive proteomic characterization and functional annotation of Siberian sturgeon seminal plasma proteins

Siberian sturgeon (Acipenser baerii) is considered the most valuable species in aquaculture. The uniqueness of sturgeon reproduction implicates the need for studying semen composition at the protein level. Seminal plasma supports and protects the viability, motility and fertilizing capacity of spermatozoa by creating the optimal environment for storage and might be a rich source of biomarkers of reproductive physiology and/or disorders in male fishes. To our knowledge, there are no reports on the in-depth characterization of sturgeon seminal plasma proteins. The present study is the first to describe the in-depth proteomic characterization of Siberian sturgeon seminal plasma using two complementary proteomic approaches: gel-based (2DE and 2D blue native (BN)/SDS–PAGE) and gel-free (LC–MS/MS). LC–MS/MS allowed the identification of 657 proteins and 339 protein spots were identified after 2DE (almost 60% were present in various proteoforms). Combining the two proteomic strategies, we identified 665 proteins with high confidence (false positive rate below 1%), producing the largest catalogue of proteins from sturgeon seminal plasma to date. For the first time, we demonstrated interactions between seminal plasma proteins; four multiprotein complexes (MC1-MC4) were identified after 2D BN/SDS–PAGE, including (MC1) serotransferrin-2 (TF) and fish-egg lectin (FEL); (MC2) serum albumin 2 (ALB) and retinol-binding protein 4 (RBP4); (MC3) ALB and TF; and (MC4) apolipoprotein A-I (APOA1), riboflavin-binding protein (RfBP) and myoglobin (MB). BN/SDS–PAGE also revealed that immunoglobulin and TF formed homomultimeric (dimer, trimer, tetramer and pentamer) complexes in seminal plasma. ALB, TF, beta-Ala-His dipeptidase (CNDP1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), IGH, APOA1, hemopexin (HPX), type-4 ice-structuring protein (AFP4), FEL, RfBP, ovochymase 2 (OVCH2) and glycogen phosphorylase, liver form-like (PYGL) were selected as major seminal plasma proteins. The functional analysis of the identified proteins indicated their involvement mainly in immune system processes and response to stimulus, metabolism, vesicle-mediated transport, proteolysis, and cadherin binding involved in cell–cell adhesion. Moreover, 69 proteins were associated with reproductive processes, including spermatogenesis, fertilization, acrosomal reaction and sperm motility. Comparative proteomic analysis of sturgeon seminal plasma showed common proteins between fish and humans and 172 proteins specific for sturgeons, which may reflect the specificity of sturgeon reproduction. To conclude, this integrative proteomic view offers a deeper insight into the physiological function of seminal plasma and processes occurring in the sturgeon reproductive tract. The availability of a catalogue of sturgeon seminal plasma proteins opens the way to future research into development of new biomarkers and possible application in the improvement of methods of controlled reproduction. The mass spectrometry proteomics data have been deposited into ProteomeXchange with the identifier PXD035351.

MII(H2dapsc)]-[Cr(CN)6] (M = Mn, Co) Chain and Trimer Complexes: Synthesis, Crystal Structure, Non-Covalent Interactions and Magnetic Properties.

Four new heterometallic complexes combining [MII(H2dapsc)]2+ cations with the chelating H2dapsc {2,6-diacetylpyridine-bis(semicarbazone)} Schiff base ligand and [Cr(CN)6]3- anion were synthesized: {[MII(H2dapsc)]CrIII(CN)6K(H2O)2.5(EtOH)0.5}n·1.2n(H2O), M = Mn (1) and Co (2), {[Mn(H2dapsc)]2Cr(CN)6(H2O)2}Cl·H2O (3) and {[Co(H2dapsc)]2Cr(CN)6(H2O)2}Cl·2EtOH·3H2O (4). In all the compounds, M(II) centers are seven-coordinated by N3O2 atoms of H2dapsc in the equatorial plane and N or O atoms of two apical -CN/water ligands. Crystals 1 and 2 are isostructural and contain infinite negatively charged chains of alternating [MII(H2dapsc)]2+ and [CrIII(CN)6]3- units linked by CN-bridges. Compounds 3 and 4 consist of centrosymmetric positively charged trimers in which two [MII(H2dapsc)]2+ cations are bound through one [CrIII(CN)6]3- anion. All structures are regulated by π-stacking of coplanar H2dapsc moieties as well as by an extensive net of hydrogen bonding. Adjacent chains in 1 and 2 interact also by coordination bonds via a pair of K+ ions. The compounds containing MnII (1, 3) and CoII (2, 4) show a significant difference in magnetic properties. The ac magnetic measurements revealed that complexes 1 and 3 behave as a spin glass and a field-induced single-molecule magnet, respectively, while 2 and 4 do not exhibit slow magnetic relaxation in zero and non-zero dc fields. The relationship between magnetic properties and non-covalent interactions in the structures 1-4 was traced.

Neutralization Epitopes in Trimer and Pentamer Complexes Recognized by Potent Cytomegalovirus-Neutralizing Human Monoclonal Antibodies.

Human cytomegalovirus (HCMV) infects 36% to almost 100% of adults and causes severe complications only in immunocompromised individuals. HCMV viral surface trimeric (gH/gL/gO) and pentameric (gH/gL/UL128/UL130/UL131A) complexes play important roles in HCMV infection and tropism. Here, we isolated and identified a total of four neutralizing monoclonal antibodies (MAbs) derived from HCMV-seropositive blood donors. Based on their reactivity to HCMV trimer and pentamer, these MAbs can be divided into two groups. MAbs PC0012, PC0014, and PC0035 in group 1 bind both trimer and pentamer and neutralize CMV by interfering with the postattachment steps of CMV entering into cells. These three antibodies recognize antigenic epitopes clustered in a similar area, which are overlapped by the epitope recognized by the known neutralizing antibody MSL-109. MAb PC0034 in group 2 binds only to pentamer and neutralizes CMV by blocking the binding of pentamer to cells. Epitope mapping using pentamer mutants showed that amino acid T94 of the subunit UL128 and K27 of UL131A on the pentamer are key epitope-associated residues recognized by PC0034. This study provides new evidence and insight information on the importance of the development of the CMV pentamer as a CMV vaccine. In addition, these newly identified potent CMV MAbs can be attractive candidates for development as antibody therapeutics for the prevention and treatment of HCMV infection. IMPORTANCE The majority of the global population is infected with HCMV, but severe complications occur only in immunocompromised individuals. In addition, CMV infection is a major cause of birth defects in newborns. Currently, there are still no approved prophylactic vaccines or therapeutic monoclonal antibodies (MAbs) for clinical use against HCMV infection. This study identified and characterized a panel of four neutralizing MAbs targeting the HCMV pentamer complex with specific aims to identify a key protein(s) and antigenic epitopes in the HCMV pentamer complex. The study also explored the mechanism by which these newly identified antibodies neutralize HCMV in order to design better HCMV vaccines focusing on the pentamer and to provide attractive candidates for the development of effective cocktail therapeutics for the prevention and treatment of HCMV infection.

High light-induced changes in thylakoid supercomplexes organization from cyclic electron transport mutants of Chlamydomonas reinhardtii

The localization of carotenoids and macromolecular organization of thylakoid supercomplexes have not been reported yet in Chlamydomonas reinhardtii WT and cyclic electron transport mutants (pgrl1 and pgr5) under high light. Here, the various pigments, protein composition, and pigment-protein interactions were analyzed from the cells, thylakoids, and sucrose density gradient (SDG) fractions. Also, the supercomplexes of thylakoids were separated from BN-PAGE and SDG. The abundance of light-harvesting complex (LHC) II trimer complexes and pigment-pigment interaction were changed slightly under high light, shown by circular dichroism. However, a drastic change was seen in photosystem (PS)I-LHCI complexes than PSII complexes, especially in pgrl1 and pgr5. The lutein and β-carotene increased under high light in LHCII trimers compared to other supercomplexes, indicating that these pigments protected the LHCII trimers against high light. However, the presence of xanthophylls, lutein, and β-carotene was less in PSI-LHCI, indicating that pigment-protein complexes altered in high light. Even the real-time PCR data shows that the pgr5 mutant does not accumulate zeaxanthin dependent genes under high light, which shows that violaxanthin is not converting into zeaxanthin under high light. Also, the protein data confirms that the LHCSR3 expression is absent in pgr5, however it is presented in LHCII trimer in WT and pgrl1. Interestingly, some of the core proteins were aggregated in pgr5, which led to change in photosynthesis efficiency in high light.

A comprehensive theoretical analysis on the intermolecular hydrogen bond interactions with the Lewis bases having multiple hydrogen bonding abilities

AbstractThis work comprehensively studies the intermolecular H … O and H … N hydrogen bonding (HB) interactions between 3H‐pyrrol‐3‐one as a computationally simple model Lewis base (LB) comprising two different basic centers (sp2 hybridized O and N atoms) and hydrogen halides (Hal‐H, Hal = F, Cl, Br, and I) as common Lewis acids (LAs). In an equimolar mixture of LB and any of LAs, the formation of H … O and H … N HBs can compete with each other over the course of binary (dimer) complexation processes. Computed values of counterpoise‐corrected interaction energies (CP‐IE) together with energy decomposition analysis (EDA) through symmetry‐adapted perturbation theory (SAPT) reveal that these HBs should be classified as “weak‐to‐medium” ones which are mainly dominated with electrostatic interactions. Among many explored correlation analyses, within the binary complexes formation, the values of CP‐IE are perfectly linearly correlated with those of electron density at the bond critical points of the mentioned HBs, , leading to two different regression equations as ‐ . These equations allow that an accurate prediction of the value of CP‐IE for H … O and H … N HBs is made feasible using the value of easily and rapidly computable without an explicit (direct) calculation of the so costly CP‐IE. Such equations, also, were used to accurately and individually predict CP‐IE values in ternary (trimer) complexes where both of approximately pairwise additive H … O and H … N HBs can be formed at once. Moreover, in terms of the calculated values of cooperativity energies, these two HBs make each other weaken portraying an anticooperativity in the ternary complexes studied.

Allosteric Determinants of the SARS-CoV-2 Spike Protein Binding with Nanobodies: Examining Mechanisms of Mutational Escape and Sensitivity of the Omicron Variant.

Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against the SARS-CoV-2 virus and resilience against mutational escape. In this study, we performed a comprehensive computational analysis of the SARS-CoV-2 spike trimer complexes with single nanobodies Nb6, VHH E, and complex with VHH E/VHH V nanobody combination. We combined coarse-grained and all-atom molecular simulations and collective dynamics analysis with binding free energy scanning, perturbation-response scanning, and network centrality analysis to examine mechanisms of nanobody-induced allosteric modulation and cooperativity in the SARS-CoV-2 spike trimer complexes with these nanobodies. By quantifying energetic and allosteric determinants of the SARS-CoV-2 spike protein binding with nanobodies, we also examined nanobody-induced modulation of escaping mutations and the effect of the Omicron variant on nanobody binding. The mutational scanning analysis supported the notion that E484A mutation can have a significant detrimental effect on nanobody binding and result in Omicron-induced escape from nanobody neutralization. Our findings showed that SARS-CoV-2 spike protein might exploit the plasticity of specific allosteric hotspots to generate escape mutants that alter response to binding without compromising activity. The network analysis supported these findings showing that VHH E/VHH V nanobody binding can induce long-range couplings between the cryptic binding epitope and ACE2-binding site through a broader ensemble of communication paths that is less dependent on specific mediating centers and therefore may be less sensitive to mutational perturbations of functional residues. The results suggest that binding affinity and long-range communications of the SARS-CoV-2 complexes with nanobodies can be determined by structurally stable regulatory centers and conformationally adaptable hotspots that are allosterically coupled and collectively control resilience to mutational escape.

Dynamical Behavior of Aromatic Trimer Complexes in Unimolecular Dissociation Reaction at High Temperatures. Case Studies on C6H6-C6F6-C6H6 and C6H6 Trimer Complexes.

The intramolecular vibrational energy redistribution (IVR) dynamics during unimolecular dissociation of aromatic trimers at high temperatures is the primary interest of this study. Chemical dynamics simulations are performed for the unimolecular dissociation of benzene-hexafluorobenzene-benzene (Bz-HFB-Bz) and benzene trimer (Bz-trimer) complexes at a temperature range of 1000-2000 K. Partial dissociation of both the complexes is observed, which leads to a dimer and a monomer in the dynamics. However, the probability of such dissociation was found much lower in the case of the Bz-trimer, which further decreases with the increase of temperature. The rate of partial dissociation of Bz-HFB-Bz is faster at 1500, 1800, and 2000 K, whereas the rate of complete dissociation of the Bz-trimer is significantly faster than Bz-HFB-Bz at all temperatures. This is just the opposite of the corresponding dimer's dissociation, where benzene-hexafluorobenzene (Bz-HFB) dissociates at a faster rate than the benzene dimer (Bz-dimer). Thus, the dissociation dynamics of the trimer is different than that of the dimer. Simulations with excited intramolecular and intermolecular modes of the trimer complexes reveal that energy flows from intermolecular to intramolecular modes of Bz-HFB-Bz more freely than the Bz-trimer, and the dissociation process becomes slower for the former. Calculated activation energies for both types of dynamics are much lower than the corresponding binding energies, which may be due to the anharmonicity. The Arrhenius equation with an anharmonic correction factor is considered to recalculate the activation energy and pre-exponential factor.

Collective residue interactions in trimer complexes of SARS-CoV-2 spike proteins analyzed by fragment molecular orbital method

In large biomolecular systems such as protein complexes, there are huge numbers of combinations of inter-residue interactions whose comprehensive analyses are often beyond the intuitive processing by researchers. Here we propose a computational method to allow for a systematic analysis of these interactions based on the fragment molecular orbital calculations, in which the inter-fragment interaction energies are comprehensively processed by the singular value decomposition. For a trimer complex of SARS-CoV-2 spike protein, three-body interactions among residues belonging to three chains are analyzed to elicit a small number of essential interaction modes or networks crucial for the structural stability of the complex.

Cryo-Electron Microscopy Structure and Interactions of the Human Cytomegalovirus gHgLgO Trimer with Platelet-Derived Growth Factor Receptor Alpha.

ABSTRACTHuman cytomegalovirus (HCMV) is a herpesvirus that produces disease in transplant patients and newborn children. Entry of HCMV into cells relies on gH/gL trimer (gHgLgO) and pentamer (gHgLUL128–131) complexes that bind cellular receptors. Here, we studied the structure and interactions of the HCMV trimer, formed by AD169 strain gH and gL and TR strain gO proteins, with the human platelet-derived growth factor receptor alpha (PDGFRα). Three trimer surfaces make extensive contacts with three PDGFRα N-terminal domains, causing PDGFRα to wrap around gO in a structure similar to a human hand, explaining the high-affinity interaction. gO is among the least conserved HCMV proteins, with 8 distinct genotypes. We observed high conservation of residues mediating gO-gL interactions but more extensive gO variability in the PDGFRα interface. Comparisons between our trimer structure and a previously determined structure composed of different subunit genotypes indicate that gO variability is accommodated by adjustments in the gO-PDGFRα interface. We identified two loops within gO that were disordered and apparently glycosylated, which could be deleted without disrupting PDGFRα binding. We also identified four gO residues that contact PDGFRα, which when mutated produced markedly reduced receptor binding. These residues fall within conserved contact sites of gO with PDGFRα and may represent key targets for anti-trimer neutralizing antibodies and HCMV vaccines. Finally, we observe that gO mutations distant from the gL interaction site impact trimer expression, suggesting that the intrinsic folding or stability of gO can impact the efficiency of trimer assembly.

Infrared spectroscopy of the protonated HCl dimer and trimer.

The protonated HCl dimer and trimer complexes were prepared by pulsed discharges in supersonic expansions of helium or argon doped with HCl and hydrogen. The ions were mass selected in a reflectron time-of-flight spectrometer and investigated with photodissociation spectroscopy in the IR and near-IR regions. Anharmonic vibrational frequencies were computed with VPT2 at the MP2/cc-pVTZ level of theory. The Cl-H stretching fundamentals and overtones were measured in addition to stretch-torsion combinations. VPT2 theory at this level confirms the proton-bound structure of the dimer complex and provides a reasonably good description of the anharmonic vibrations in this system. The trimer has a HCl-HClH+-ClH structure in which a central chloronium ion is solvated by two HCl molecules via hydrogen bonding. VPT2 reproduces anharmonic frequencies for this system, including several combinations involving core ion Cl-H stretches, but fails to describe the relative band intensities.

Interactions between isocyanic acid and atmospheric acidic, neutral and basic species

The properties of atmospheric nucleation precursors have effects on the physical and chemical behavior of particulate matter. However, molecular understanding of how acidic, neutral and basic gas molecules impact the new particle formation in the atmosphere is rarely considered. In this study, we present the DFT and CCSD(T) study of the hydrogen bonding interactions of HNCO with a neutral species (water), two acidic species (sulfuric acid, hydrogen sulfide), and a basic species (methylamine). The formation of dimer, trimer, tetramer, and pentamer complexes was investigated. The binding energies clearly reveal that the methylamine interacts with HNCO more strongly than H2S and H2O. Due to the strong interactions, the diameters of clusters studied can substantially increase from about ~1–2 Å (dimers) to more than 10 Å (pentamers).

STUDY OF THE MOLECULAR STRUCTURE OF VALINE BY QUANTUMCHEMICAL CALCULATIONS

In this paper, calculations were performed in an isolated system using ab initio and Density Functional Theory (DFT) approaches to investigate the mechanism of molecular complex formation in valine, an amino acid. Calculations have represented that the valine molecule has intramolecular hydrogen bonds and that intermolecular hydrogen bonds are used to generate dimer and trimer complexes. The Raman spectral line (?? (OH) = 3749 cm−1 ) corresponding to the O-H vibration of the valine molecule shifted to a lower frequency of 343.9 cm-1 at the O-H bond in the trimer complex and 1533.2 cm-1 at the O-H bond due to intermolecular hydrogen bonding

Integrated Biophysical Modeling of the SARS-CoV-2 Spike Protein Binding and Allosteric Interactions with Antibodies.

Structural and biochemical studies of the severe acute respiratory syndrome (SARS)-CoV-2 spike glycoproteins and complexes with highly potent antibodies have revealed multiple conformation-dependent epitopes highlighting conformational plasticity of spike proteins and capacity for eliciting specific binding and broad neutralization responses. In this study, we used coevolutionary analysis, molecular simulations, and perturbation-based hierarchical network modeling of the SARS-CoV-2 spike protein complexes with a panel of antibodies targeting distinct epitopes to explore molecular mechanisms underlying binding-induced modulation of dynamics and allosteric signaling in the spike proteins. Through coevolutionary analysis of the SARS-CoV-2 spike proteins, we identified highly coevolving hotspots and functional clusters that enable a functional cross-talk between distant allosteric regions in the SARS-CoV-2 spike complexes with antibodies. Coarse-grained and all-atom molecular dynamics simulations combined with mutational sensitivity mapping and perturbation-based profiling of the SARS-CoV-2 receptor-binding domain (RBD) complexes with CR3022 and CB6 antibodies enabled a detailed validation of the proposed approach and an extensive quantitative comparison with the experimental structural and deep mutagenesis scanning data. By combining in silico mutational scanning, perturbation-based modeling, and network analysis of the SARS-CoV-2 spike trimer complexes with H014, S309, S2M11, and S2E12 antibodies, we demonstrated that antibodies can incur specific and functionally relevant changes by modulating allosteric propensities and collective dynamics of the SARS-CoV-2 spike proteins. The results provide a novel insight into regulatory mechanisms of SARS-CoV-2 S proteins showing that antibody-escaping mutations can preferentially target structurally adaptable energy hotspots and allosteric effector centers that control functional movements and allosteric communication in the complexes.

Absorption of Naphthalene by Leaves and Its Interaction with Chlorophyll–Protein Complexes of Pea Plants

Mechanisms of photosynthesis inhibition by vaporous naphthalene, its permeation into thylakoids, and interactions with chlorophyll–protein complexes were studied. It was found that vaporous naphthalene is first adsorbed on the pea (Pisum sativum L.) leaf’s surface and then penetrates into the leaf, binds to thylakoids, and inhibits photosynthesis. The adsorbed naphthalene can be washed from the leaf surface by means of short-term (1 min) incubation of leaves in hexane. When thylakoids isolated from such leaves were exposed to UV light with the peak intensity at 266 nm, the emission bands at 325 nm and 335 nm corresponding to naphthalene fluorescence in water were detected. Nondenaturing PAGE was applied to isolate chlorophyll–protein complexes (CPC). In the gels thus obtained, neither of the green zones emitted naphthalene fluorescence, which was ascribed to fluorescence quenching by CPC components absorbing light at 266 nm. However, when CPC-containing gels were exposed to UV light, chlorophyll bleaching developed faster in naphthalene-treated than in naphthalene-free samples. In addition, excitation energy transfer from naphthalene to chlorophyll was detected in light-harvesting II (LHCII) trimer complexes after washing PAAG from low-molecular fluorescence quenchers. Thus, vaporous naphthalene accumulates on the leaf surface, partially penetrates into the leaves, and binds to thylakoids and CPC. It is assumed that naphthalene–LHCII trimer interactions facilitate energy transfer from naphthalene to chlorophyll, thereby enhancing chlorophyll photobleaching and inhibition of photosynthesis.

Molecular Electrostatic Potential Reorganization Theory to Describe Positive Cooperativity in Noncovalent Trimer Complexes.

Supramolecular self-assembly and molecular recognition processes are driven mainly by positive cooperativity in noncovalent interactions. Here, we report a large variety of hydrogen-, tetrel-, chalcogen-, pnicogen-, halogen-, aerogen-, and dihydrogen-bonded dimer and trimer complexes, computed using the MP2/6-311++G(d,p) level ab initio theory. The dimer to trimer change is associated with a positive cooperativity in all the complexes. Significant electron density reorganization occurs in monomers because of noncovalent bond formation which is quantified using the change in the molecular electrostatic potential (MESP) at bonded atoms. For a noncovalent dimer XDYA, an electron density flow is observed from the donor molecule XD to acceptor molecule YA. As a result, YA in dimer showed a tendency to form a stronger noncovalent bond with an electron-deficient center of a third molecule, whereas XD in the dimer showed a tendency to form a stronger noncovalent bond with an electron-rich center of a third molecule. The change in change-of-MESP at the donor and acceptor atoms involved in bond formation (ΔΔVn) is used as a parameter to assess the extent of electron donor-acceptor (eDA) interaction in dimers and trimers and found that ΔΔVn is directly proportional to the total binding energy. A cooperativity rule has emerged from this study which states that the electron reorganization in the dimer due to the eDA interaction always enhances its donor-acceptor interactive behavior with a third molecule toward the formation of a noncovalent trimer complex.