C1 Complex Research Articles

Quantification of soil losses and multivariate statistics of factors controlling water erosion (Allal Al Fassi watershed, Morocco)

In order to preserve water resources and conserve agricultural land and biodiversity, a precise assessment of soil losses is necessary. It is for this reason that the empirical model of revised RUSLE soil loss equation was applied in order to quantify and describe the rate of erosion in Allal Al Fassi watershed, located in the Middle Atlas mountain chain (Morocco). To understand and define the relationships between water erosion and the factors aggravating its dynamics in Allal Al Fassi watershed, the use of multivariate statistics is in fact an integral part. Sub-models have been adopted to calculate factors of R erosivity, K erodibility, LS slope length and steepness, C soil conservation, and P anti-erosion practices using field data, remote sensing, and GIS (geographic information systems). The map of soil losses resulting from RUSLE model allows us to distinguish five classes. The average annual soil losses are estimated to be 624.07 t ha−1 year−1, with a wide range that goes from 3.57 to 3521.07 t ha−1 year−1 and a median equal to 335.48 t ha−1 y−1. They are greater upstream of watershed, mainly in the eastern part, where slopes are steep and long and soil are highly erodible with little or no development despite very variable conservation and very low to low erosion. However, they are low in areas with low to very low erosion, slope length, and steepness and erodibility, with low anti-erosion practices and strong soil conservation. Multivariate statistical analysis has shown that soil losses in Allal Al Fassi watershed are governed by LS slope length and steepness, K erodibility, and P anti-erosion practices and that the percentages of organic matter, sands, and silts have a significant impact on the variation of soil losses. The latter prove to be important for soils type C1 complex, entisols and inceptisols, soils on dolomitic/calcareous substrate, and soils occupied by matorrals and steppes. RUSLE model has proved useful in quantifying erosion and determining the factors controlling it in Allal Al Fassi watershed, highlighting priority areas that require urgent measures (preventive or remedial) and also where erosion risk reaches irreversible stages.

Inhibition of Complement C1s with Sutimlimab in Patients with Cold Agglutinin Disease (CAD): Interim Results of the Phase 3 Cardinal Study Long-Term Follow-up

Inhibition of Complement C1s with Sutimlimab in Patients with Cold Agglutinin Disease (CAD): Interim Results of the Phase 3 Cardinal Study Long-Term Follow-up

Investigation of inclusion complex of metformin into selective cyclic peptides as novel drug delivery system: Structure, electronic properties, AIM, and NBO study via DFT

AbstractIn this study, the density functional theory computational method is used to investigate the encapsulation process of metformin into three types of the cyclic peptides composed of eight serine (CP1), eight glycine (CP2), and four serine‐glycine (CP3) cyclic peptides as a new model in the process of drug delivery in the gas phase. The obtained results using the B3LYP/6‐31++G (d,p) method indicate that the complexes formed are energetically favored. Furthermore, results reveal that the drug encapsulation process is typically chemisorption. The natural bonding orbital analysis shows that the intermolecular interaction of the C2 complex (metformin/CP2) is stronger than the C1 (Metformin/CP1) and C3 (Metformin/CP3) complexes due to greater total charge transfer energy, and the C1 complex is found to be the most favored complex. The theory of atoms in molecule (AIM) method is used to analyze the nature of interactions in different molecular systems. The results show the investigated cyclic peptides as effective carriers of metformin in the nanomedicine field.

Complement evasion strategies of Borrelia burgdorferi sensu lato.

Borreliosis (Lyme disease) is a spirochetal disease caused by the species complex of Borreliaburgdorferi transmitted by Ixodes spp. ticks. Recorded to be the most common tick-borne disease in the world, the last two decades have seen an increase in disease incidence and distribution, exceeding 360000 cases in Europe alone. If untreated, infection may cause skin symptoms, arthritis, and neurological or cardiac complications. Borrelia spirochetes have developed strategies to evade the mammalian host immune system. These include the complement system, which is an important first-line defense mechanism against invading microbes. To evade the complement, spirochetes bind soluble complement regulators factor H (FH), factor H-like protein, and C4bp to their outer surfaces. B.burgdorferi spirochetes can inhibit the classical pathway of complement by the outer surface protein (Osp) BBK32, which blocks the activation of the C1 complex, composed of C1q, C1r, and C1s. The FH-binding proteins of borreliae include Osps OspE, CspA, and CspZ. Following repeated infections, antibodies against these proteins develop and may provide functional immunity against borreliosis. This review discusses critical immune evasion strategies, focusing on complement evasion by borreliae.

Real-time tracking reveals catalytic roles for the two DNA binding sites of Rad51

During homologous recombination, Rad51 forms a nucleoprotein filament on single-stranded DNA to promote DNA strand exchange. This filament binds to double-stranded DNA (dsDNA), searches for homology, and promotes transfer of the complementary strand, producing a new heteroduplex. Strand exchange proceeds via two distinct three-strand intermediates, C1 and C2. C1 contains the intact donor dsDNA whereas C2 contains newly formed heteroduplex DNA. Here, we show that the conserved DNA binding motifs, loop 1 (L1) and loop 2 (L2) in site I of Rad51, play distinct roles in this process. L1 is involved in formation of the C1 complex whereas L2 mediates the C1–C2 transition, producing the heteroduplex. Another DNA binding motif, site II, serves as the DNA entry position for initial Rad51 filament formation, as well as for donor dsDNA incorporation. Our study provides a comprehensive molecular model for the catalytic process of strand exchange mediated by eukaryotic RecA-family recombinases.

Macrophage production and activity of innate immune proteins C1q, C1r, and C1s are modulated in response to molecular patterns

Abstract Pattern recognition receptors of the complement system, such as C1q, are vital for clearance of foreign and altered-self targets. C1q has a dual role in vivo: activating the inflammatory classical complement pathway via C1 complex formation (C1qC1r2C1s2) and opsonization in the absence of C1r and C1s which is anti-inflammatory. We hypothesize that macrophages encountering foreign targets will increase levels of C1 subunits to activate C1 and mount an inflammatory response while macrophages encountering damaged-self targets may only increase C1q production to promote anti-inflammatory responses and clearance. Human monocyte derived macrophages (HMDM) were incubated with LPS, E. coli bioparticles, oxLDL, apoptotic cells or polarized into M1 or M2 HMDMs. RNA was isolated for qPCR and supernatant for Luminex protein analysis, ELISA, and C1(q) hemolytic titers. Data show that M1 HMDM increase C1r and C1s mRNA, and produce higher levels of active C1 than M0 HMDM. In contrast, there is no change in gene or protein expression of C1 subunits in M2 HMDM. HMDM treatment with foreign targets revealed a trend of increased C1r and C1s mRNA, and decreased C1q mRNA, but not at the protein level. Treatments with damaged-self targets varied; as hypothesized, C1q gene and protein expression increases in response to apoptotic cells, however there are no substantial changes in treatments with oxLDL. Significant levels of active C1q, but not C1, were detected in response to LPS, oxLDL, and apoptotic cells. Data suggests there is modulation of C1 subunit production and activity in response to different targets. C1q production in the absence of C1r and C1s may be important in resolving inflammation during clearance of apoptotic cells, thus avoiding autoimmunity.

Sub-Hermitian geometry and the quantitative Newlander-Nirenberg theorem

Given a finite collection of C1 complex vector fields on a C2 manifold M such that they and their complex conjugates span the complexified tangent space at every point, the classical Newlander-Nirenberg theorem gives conditions on the vector fields so that there is a complex structure on M with respect to which the vector fields are T0,1. In this paper, we give intrinsic, diffeomorphic invariant, necessary and sufficient conditions on the vector fields so that they have a desired level of regularity with respect to this complex structure (i.e., smooth, real analytic, or have Zygmund regularity of some finite order). By addressing this in a quantitative way we obtain a holomorphic analog of the quantitative theory of sub-Riemannian geometry initiated by Nagel, Stein, and Wainger. We call this sub-Hermitian geometry. Moreover, we proceed more generally and obtain similar results for manifolds which have an associated formally integrable elliptic structure. This allows us to introduce a setting which generalizes both the real and complex theories.

Coordination properties of two new Schiff-base phenoxy-carboxylates and comparative study of their antioxidant activities

Two novel tridentate Schiff-base ligands containing carboxylate groups were obtained from the condensation of 3-amino-4-hydroxybenzoic acid with either acetylacetone (H3L1) or salicylaldehyde (H3L2). H3L1 reacted with copper(II) acetate and pyridine (strongly coordinating solvent) to afford the C1 complex, while reaction of H3L2 with nickel(II) acetate and pyridine afforded two types of complexes C2 and C3. The two ligands and their metal complexes were fully characterized by elemental analysis, XRD and spectroscopic analysis. Upon its fully deprotonated state, (L1)3− coordinates in a keto-enamine fashion and acts as a ditopic binder through an ONO tridentate donor system and an O monodentate donor system (carboxylate). Upon its doubly deprotonated state, (HL2)2− ligand acts either as monotopic tridentate binder (i.e. enol-imine form with an ONO donor system that lead to complex C2) or as a ditopic ligand (ONO tridentate and O monodentate donor systems to afford complex C3). The molecular structure of all the compounds were determined by single crystal X-ray diffraction studies and revealed several important characteristics. In complex C1, the Cu(II) cations are five-coordinated with a slightly distorted square pyramidal geometry, while in C2 and C3 complexes, the Ni(II) ions are four and six–coordinated with a square planar and a slightly distorted octahedral geometry, respectively. Following this structural investigation, the antioxidant activities of the free ligands and their metal complexes were then investigated and demonstrated interesting antioxidant features especially for H3L2 and complex C3. Lastly, temperature dependent magnetic susceptibility measurements showed the presence of ferromagnetic interactions in C1 mediated through the phenoxido bridges.

In vitro assessments of cytotoxic and cytostatic effect of two [Cu(dien)(N-N)]Br2 complexes on L6, HCT, PC3 and HepG2 cancer cells

Two new Cu(II) complexes of type [Cu(dien)(N-N)] Br 2 (dien is diethlylenetriamine, C1 complex with N-N = diethlylenetriamine and C2 complex with N-N = propyl-1,3-diamine) were made valuable and in vitro screened for both cytostatic and cytotoxic activities against four cell lines: colon cancer (HCT), liver cancer (HepG2), prostate cancer (PC3) and as control cell (L6) human muscle cell was used via MTT test. The results reflected these complexes as a promising activity antiprolifrative agent against the used cell lines indicating that C1 and C2 complexes have a high anticancer activity at non-toxic concentrations.

Inhibition of Complement C1s with Sutimlimab in Patients with Cold Agglutinin Disease (CAD): Results from the Phase 3 Cardinal Study

Inhibition of Complement C1s with Sutimlimab in Patients with Cold Agglutinin Disease (CAD): Results from the Phase 3 Cardinal Study

Di-μ-oxidovanadium(V) di-nuclear complexes: Synthesis, X-ray, DFT modeling, Hirshfeld surface analysis and antioxidant activity

In this work, two di-μ-oxidovanadium(V) complexes, [(L1H)VO(μ-O)]2 (C1) and [(L2H)VO(μ-O)]2 (C2), with tridentate Schiff base ligands, [N-(2-hydroxyethylamino)ethyl]-5-methoxysalicylaldimine (L1H) and 2-[(2-(2-Hydroxyethylamino) ethylimino)methyl] phenol (L2H), respectively, were prepared and characterized by various spectroscopic techniques. The X-ray diffraction of C1 showed six-coordinate vanadium in a distorted octahedral geometry with the imine, phenolate and amine donors of the ligand and two oxo-group bonds. Density functional theory (DFT) was carried out using B3LYP level with the 6-31G basis set in order to predict the molecular structure of C1, delineate its vibrational wavenumbers and define the theoretical NMR shifts, which were performed with the GIAO approach. Thereafter, Hirshfeld surface (HS) and 2D fingerprint analysis were used to investigate the intermolecular contacts in the C1 complex. The DPPH free radical scavenging assay was used to evaluate the antioxidant activity of both C1 and C2 complexes.

C1R Mutations Trigger Constitutive Complement 1 Activation in Periodontal Ehlers-Danlos Syndrome.

Heterozygous missense or in-frame insertion/deletion mutations in complement 1 subunits C1r and C1s cause periodontal Ehlers-Danlos Syndrome (pEDS), a specific EDS subtype characterized by early severe periodontal destruction and connective tissue abnormalities like easy bruising, pretibial haemosiderotic plaques, and joint hypermobility. We report extensive functional studies of 16 C1R variants associated with pEDS by in-vitro overexpression studies in HEK293T cells followed by western blot, size exclusion chromatography and surface plasmon resonance analyses. Patient-derived skin fibroblasts were analyzed by western blot and Enzyme-linked Immunosorbent Assay (ELISA). Overexpression of C1R variants in HEK293T cells revealed that none of the pEDS variants was integrated into the C1 complex but cause extracellular presence of catalytic C1r/C1s activities. Variants showed domain-specific abnormalities of intracellular processing and secretion with preservation of serine protease function in the supernatant. In contrast to C1r wild type, and with the exception of a C1R missense variant disabling a C1q binding site, pEDS variants had different impact on the cell: retention of C1r fragments inside the cell, secretion of aggregates, or a new C1r cleavage site. Overexpression of C1R variants in HEK293T as well as western blot analyses of patient fibroblasts showed decreased levels of secreted C1r. Importantly, all available patient fibroblasts exhibited activated C1s and activation of externally added C4 in the supernatant while control cell lines secreted proenzyme C1s and showed no increase in C4 activation. The central elements in the pathogenesis of pEDS seem to be the intracellular activation of C1r and/or C1s, and extracellular presence of activated C1s that independently of microbial triggers can activate the classical complement cascade.

Upregulation of C1-inhibitor in pancreatic cancer.

The complement system has recently sparked more interest in cancer research. The classical pathway is initiated by activation of the C1 complex, which irreversibly can be bound to and inhibited by C1-INH. We have previously shown that C1-INH is upregulated in human glioblastoma (astrocytoma grade IV) on both gene and protein level. We here examine whether the complement system seems to play a role also in pancreatic cancer. We performed an expression analysis of complement associated genes in 36 pancreatic ductal adenocarcinoma tumors and matching normal pancreatic tissue samples from pancreatic cancer patients (data from the publicly available database GSE15471). C1-INH was significantly upregulated in the pancreatic cancer tissue. None of the downstream components of the cascade were significantly upregulated in the cancer samples as compared to the control samples, which is the same pattern as we found in glioblastoma. GO analysis showed that membrane attack complex came up as the second most significantly associated cellular component. Analyzing gene expression of C1-INH in the pancreatic cancer cell lines from primary tumors versus metastatic tumor revealed no difference for the two mRNA transcripts (GSE59357). Analysis of gene expression of complement related genes shows an upregulation of C1-INH and a downregulation of downstream components. This could suggest that C1-INH plays a role also in pancreatic cancer.

Complement C1r serine protease contributes to kidney fibrosis.

We have previously reported that complement activation precedes the development of kidney fibrosis; however, little is known about the cellular mechanisms involved in this transition. We hypothesized that increased expression of C1 complex protease C1r, the initiator of complement activation, contributes to tubulointerstitial fibrosis and tested this idea in mice with global deletion of C1r. Although expression of C1r in untreated wild-type (WT) mice was higher in the liver compared with kidney tissue, administration of folic acid (FA) led to upregulation of C1r mRNA and protein levels only in kidney tissue. Immunohistochemistry and in situ hybridization experiments localized increased expression of C1r and C1s proteases to renal tubular epithelial cells. C1r-null mice had reduced acute tubular injury and inflammation measured 2 days after FA administration compared with WT mice. C1r deletion reduced expression of C1s, C3 fragment formation, and organ fibrosis measured 14 days after FA administration. Differential gene expression performed in kidney tissue demonstrated that C1r-null mice had reduced expression of genes associated with the acute phase response, complement, proliferation of connective tissue cells (e.g., platelet-derived growth factor receptor-β), and reduced expression of genes associated with inflammation compared with FA-treated WT mice. In vitro experiments in renal epithelial cells demonstrated that C1s expression is dependent on increased C1r expression and that interferon-γ induces the expression of these two proteases. We conclude that increased expression of C1 complex proteases is associated with increased tissue inflammation and complement C3 formation and represents an important pathogenic mechanism leading to FA-mediated tubulointerstitial fibrosis.

Tumor Cells Hijack Macrophage-Produced Complement C1q to Promote Tumor Growth.

Clear-cell renal cell carcinoma (ccRCC) possesses an unmet medical need, particularly at the metastatic stage, when surgery is ineffective. Complement is a key factor in tissue inflammation, favoring cancer progression through the production of complement component 5a (C5a). However, the activation pathways that generate C5a in tumors remain obscure. By data mining, we identified ccRCC as a cancer type expressing concomitantly high expression of the components that are part of the classical complement pathway. To understand how the complement cascade is activated in ccRCC and impacts patients' clinical outcome, primary tumors from three patient cohorts (n = 106, 154, and 43), ccRCC cell lines, and tumor models in complement-deficient mice were used. High densities of cells producing classical complement pathway components C1q and C4 and the presence of C4 activation fragment deposits in primary tumors correlated with poor prognosis. The in situ orchestrated production of C1q by tumor-associated macrophages (TAM) and C1r, C1s, C4, and C3 by tumor cells associated with IgG deposits, led to C1 complex assembly, and complement activation. Accordingly, mice deficient in C1q, C4, or C3 displayed decreased tumor growth. However, the ccRCC tumors infiltrated with high densities of C1q-producing TAMs exhibited an immunosuppressed microenvironment, characterized by high expression of immune checkpoints (i.e., PD-1, Lag-3, PD-L1, and PD-L2). Our data have identified the classical complement pathway as a key inflammatory mechanism activated by the cooperation between tumor cells and TAMs, favoring cancer progression, and highlight potential therapeutic targets to restore an efficient immune reaction to cancer.

Inefficient and abortive classical complement pathway activation by the calcium inositol hexakisphosphate component of the Echinococcus granulosus laminated layer

Persistent extracellular tissue-dwelling pathogens face the challenge of antibody-dependent activation of the classical complement pathway (CCP). A prime example of this situation is the larva of the cestode Echinococcus granulosus sensu lato, causing cystic echinococcosis. This tissue-dwelling, bladder-like larva is bounded by a cellular layer protected by the outermost acellular “laminated layer” (LL), to which host antibodies bind. The LL is made up of a mucin meshwork and interspersed nano-deposits of calcium inositol hexakisphosphate (calcium InsP6). We previously reported that calcium InsP6 bound C1q, apparently initiating CCP activation. The present work dissects CCP activation on the LL. Most of the C1 binding activity in the LL corresponded to calcium InsP6, and this binding was enhanced by partial proteolysis of the mucin meshwork. The remaining C1 binding activity was attributable to host antibodies, which included CCP-activating IgG isotypes. Calcium InsP6 made only a weak contribution to early CCP activation on the LL, suggesting inefficient C1 complex activation as reported for other polyanions. CCP activation on calcium InsP6 gave rise to a dominant population of C3b deposited onto calcium InsP6 itself that appeared to be quickly inactivated. Apparently as a result of inefficient initiation plus C3b inactivation, calcium InsP6 made no net contribution to C5 activation. We propose that the LL protects the underlying parasite cells from CCP activation through the combined effects of inefficient permeation of C1 through the mucins and C1 retention on calcium InsP6. This mechanism does not result in C5 activation, which is known to drive parasite-damaging inflammation.

Complement C4 Prevents Viral Infection through Capsid Inactivation

SummaryThe complement system is vital for anti-microbial defense. In the classical pathway, pathogen-bound antibody recruits the C1 complex (C1qC1r2C1s2) that initiates a cleavage cascade involving C2, C3, C4, and C5 and triggering microbial clearance. We demonstrate a C4-dependent antiviral mechanism that is independent of downstream complement components. C4 inhibits human adenovirus infection by directly inactivating the virus capsid. Rapid C4 activation and capsid deposition of cleaved C4b are catalyzed by antibodies via the classical pathway. Capsid-deposited C4b neutralizes infection independent of C2 and C3 but requires C1q antibody engagement. C4b inhibits capsid disassembly, preventing endosomal escape and cytosolic access. C4-deficient mice exhibit heightened viral burdens. Additionally, complement synergizes with the Fc receptor TRIM21 to block transduction by an adenovirus gene therapy vector but is partially restored by Fab virus shielding. These results suggest that the complement system could be altered to prevent virus infection and enhance virus gene therapy efficacy.

Structural determination of the complement inhibitory domain of Borrelia burgdorferi BBK32 provides insight into classical pathway complement evasion by Lyme disease spirochetes.

The carboxy-terminal domain of the BBK32 protein from Borrelia burgdorferi sensu stricto, termed BBK32-C, binds and inhibits the initiating serine protease of the human classical complement pathway, C1r. In this study we investigated the function of BBK32 orthologues of the Lyme-associated Borrelia burgdorferi sensu lato complex, designated BAD16 from B. afzelii strain PGau and BGD19 from B. garinii strain IP90. Our data show that B. afzelii BAD16-C exhibits BBK32-C-like activities in all assays tested, including high-affinity binding to purified C1r protease and C1 complex, and potent inhibition of the classical complement pathway. Recombinant B. garinii BGD19-C also bound C1 and C1r with high-affinity yet exhibited significantly reduced in vitro complement inhibitory activities relative to BBK32-C or BAD16-C. Interestingly, natively produced BGD19 weakly recognized C1r relative to BBK32 and BAD16 and, unlike these proteins, BGD19 did not confer significant protection from serum killing. Site-directed mutagenesis was performed to convert BBK32-C to resemble BGD19-C at three residue positions that are identical between BBK32 and BAD16 but different in BGD19. The resulting chimeric protein was designated BXK32-C and this BBK32-C variant mimicked the properties observed for BGD19-C. To query the disparate complement inhibitory activities of BBK32 orthologues, the crystal structure of BBK32-C was solved to 1.7Å limiting resolution. BBK32-C adopts an anti-parallel four-helix bundle fold with a fifth alpha-helix protruding from the helical core. The structure revealed that the three residues targeted in the BXK32-C chimera are surface-exposed, further supporting their potential relevance in C1r binding and inhibition. Additional binding assays showed that BBK32-C only recognized C1r fragments containing the serine protease domain. The structure-function studies reported here improve our understanding of how BBK32 recognizes and inhibits C1r and provide new insight into complement evasion mechanisms of Lyme-associated spirochetes of the B. burgdorferi sensu lato complex.

A maize cytochrome b-c1 complex subunit protein ZmQCR7 controls variation in the hypersensitive response.

The gene GRMZM2G318346 which encodes a cytochrome b-c1 complex subunit 7 is associated with variation in strength of the hypersensitive response in maize. We previously identified a QTL at 3,545,354bp (B73 reference genome V2) on maize chromosome 5 associated with variation in the hypersensitive response (HR) conferred by the autoactive R-gene Rp1-D21 (Olukolu et al. in PLoS Genet 10:e1004562 2014). In this study, we show that a gene at this locus, GRMZM2G318346 which encodes a cytochrome b-c1 complex subunit seven (ZmQCR7), an important part of the mitochondrial electron transport chain, can suppress HR mediated by Rp1-D21 in a transient expression assay. ZmQCR7 alleles from two maize lines, W22 and B73 differ for the encoded proteins at just two sites, amino acid 27 (threonine and alanine in B73 and W22, respectively) and amino acid 109 (asparagine and serine), however, the B73 allele is much more effective at suppressing HR. We show that variation at amino acid 27 controlled this variation in HR-suppressing effects. We furthermore demonstrate that the B73 allele of ZmQCR7 can suppress HR induced by RPM1(D505V), another autoactive R-gene, and that Arabidopsis homologs of ZmQCR7 can also suppress NLR-induced HR. The implications of these findings are discussed.

Insights into the inhibitory mechanism of a resveratrol and clioquinol hybrid against Aβ42 aggregation and protofibril destabilization: A molecular dynamics simulation study

Amyloid-β (Aβ) peptide instinctively aggregate and form plaques in the brain of Alzheimer’s disease (AD) patients. At present, there is no cure or treatment for AD, and significant effort has, therefore, been made to discover potent drugs against AD. Previous studies reported that a resveratrol and clioquinol hybrid compound [(E)-5-(4-hydroxystyryl)quinolone-8-ol], C1, strongly inhibit Aβ42 aggregation and disassemble preformed fibrils. However, the atomic level details of the inhibitory mechanism of C1 against Aβ42 aggregation and protrofibril disassembly remains elusive. In this regard, molecular docking and molecular dynamics (MD) simulation of Aβ42 monomer, Aβ42 monomer–C1 complex, Aβ42 protofibril, and Aβ42 protofibril–C1 complex were performed in the present study. MD simulations highlighted that C1 bind in the central hydrophobic core (CHC) region, i.e., KLVFF (16–20) of Aβ42 monomer, which plays a critical role in Aβ42 aggregation. C1 promote the formation of native helical conformation in the Aβ42 monomer and decrease the probability of D23–K28 salt bridge interaction that is critical in the formation of aggregation-prone β-sheet conformation. Further, C1 destabilize Aβ42 protofibril structure by increasing the interchain distance between chains A–B, disrupting the salt–bridge interaction between D23–K28, and decreasing the number of backbone hydrogen bonds between chains A–B of the Aβ42 protofibril structure. The insights into the underlying inhibitory mechanism of small molecules that display potential in vitro anti–aggregation activity against Aβ42 will be beneficial for the rational design of more potent drug molecules against AD.Communicated by Ramaswamy H. Sarma