Polypeptide Sequence Research Articles

Protein Design by Integrating Machine Learning and Quantum-Encoded Optimization

The protein design problem involves finding polypeptide sequences folding into a given three-dimensional structure. Its rigorous algorithmic solution is computationally demanding, involving a nested search in sequence and structure spaces. Structure searches can now be bypassed thanks to recent machine-learning breakthroughs, which have enabled accurate and rapid structure predictions. Similarly, sequence searches might be entirely transformed by the advent of quantum annealing machines and by the required new encodings of the search problem, which could be performative even on classical machines. In this work, we introduce a general protein design scheme where algorithmic and technological advancements in machine learning and quantum-inspired algorithms can be integrated, and an optimal physics-based scoring function is iteratively learned. In this first proof-of-concept application, we apply the iterative method to a lattice protein model amenable to exhaustive benchmarks, finding that it can rapidly learn a physics-based scoring function and achieve promising design performances. Strikingly, our quantum-inspired reformulation outperforms conventional sequence optimization even when adopted on classical machines. The scheme is general and can be extended, e.g., to encompass off-lattice models, and it can integrate progress on various computational platforms, thus representing a new paradigm approach for protein design. Published by the American Physical Society 2024

Human collagen sequence polypeptides mediated biomineralization and its molecular mechanism

Biotechnology provides alternatives for regenerative medicine with more controllable functions. Herein, the polypeptides encoded with human collagen I amino-acid sequences were studied for the first time to modulate biomimetic hydroxyapatite (HAP). With a length of 50–100 nm and a width of 20–30 nm, the HAP crystal formed was plate-like. The interaction of the human collagen sequence polypeptide on the (001), (100), and (211) crystal faces of HAP crystal had been studied using Molecular Dynamics (MD) simulations, respectively. Based on MD simulations, van der Waals forces and hydrogen bonds are the main interactions between polypeptides and HAP through the –NH2, –CH2–, –OH, and –COOH, respectively. According to the calculated results, der Waals forces might be the main interaction. The human collagen sequence polypeptides exhibited the highest adsorption energy on the (001) plane of HAP, significantly higher than any of the adsorption energy on the (100) and (211) planes. Therefore, the growth of the (001) would be inhibited, which kept accurate with the result of images from the Transmission Electron Microscope (TEM). Study results provide a basis for rational designing of peptides with human collagen sequences to regenerate hard tissues.

Homologous Delta-12 Fatty Acid Desaturase (FAD2) Genes Affect Gene Expression and Linoleic Acid Levels in Lentinula edodes under Heat Stress.

Delta-12 fatty acid desaturases (FAD2s) actively regulate stress responses and cell differentiation in living organisms. In this study, six homologous FAD2 genes were identified based on the genome sequence of Lentinula edodes. Then, the six FAD2 protein sequences were analyzed using bioinformatics tools, including ExPASy ProtParam, SignalP, TMHMM, and TargetP. These analyses were performed to predict the physical and chemical properties, signal peptides, and transmembrane and conserved domains of these proteins. The polypeptide sequences were aligned, and a maximum likelihood phylogenetic tree was constructed using MEGA 7.0 software to elucidate the phylogenetic relationships between homologous FAD2 sequences. The results demonstrated that the FAD2 proteins contained three conserved histidine-rich regions (HXXXH, HXXHH, and HXXHH), which included eight histidine residues. The linoleic acid content and FAD2 enzyme activity were further analyzed, and the levels in the mutagenic heat-tolerant strain 18N44 were lower than those in the wild-type strain 18. Interestingly, the expression levels of the FAD2-2 and FAD2-3 genes under heat stress in strain 18N44 were lower than those in strain 18. These findings indicated that FAD2-2 and FAD2-3 may play major roles in the synthesis of linoleic acid during heat stress.

Characterizing the amyloid core region of the tumor suppressor protein p16INK4a using a limited proteolysis and peptide-based approach

The human tumor suppressor p16INK4a is a small monomeric protein that can form amyloid structures. Formation of p16INK4a amyloid fibrils is induced by oxidation which creates an intermolecular disulfide bond. The conversion into amyloid is associated with a change from an all α-helical structure into β-sheet fibrils. Currently, structural insights into p16INK4a amyloid fibrils are lacking. Here, we investigate the amyloid-forming regions of this tumor suppressor using isotope-labeling limited-digestion mass spectrometry analysis. We discover two key regions that likely form the structured core of the amyloid. Further investigations using thioflavin-T fluorescence assays, electron microscopy and solution nuclear magnetic resonance spectroscopy of shorter peptide regions confirm the self-assembly of the identified sequences that include methionine and leucine repeat regions. This work describes a simple approach for studying protein motifs involved in the conversion of monomeric species into aggregated fibril structures. It provides first insights into the polypeptide sequence underlying the core structure of amyloid p16INK4a formed after a unique oxidation-driven structural transition.

Cloning and characterization of the LvCTL genes encoding C-type lectin from white-leg shrimp ( Litopenaeus vannamei).

Lectins are carbohydrate-binding protein domains. The C-type lectin designates a requirement for calcium for binding. Proteins contain C-type lectin domains that have a diverse range of functions, including cell-cell adhesion, immune response to pathogens, and apoptosis. This study aimed to investigate the characters of LvCTL-encoding genes from white-leg shrimp ( Litopenaeus vannamei) in Central Vietnam. Two PCR products (LvCTL3 and LvCTL4) were cloned and sequenced. The structure and characterization of LvCTL proteins were predicted using bioinformatics tools. The results showed that the LvCTL3 gene was 444 nucleotides in length and 98.87% similar to the published LvCTL3 gene (accession number: KF156943). The polypeptide sequence had 147 amino acids, which were 97.28% identical to the reference sequence (AGV68681) and the LvCTL4 gene had a length of 417 nucleotides and homology of 99.52% compared to the published gene (KM387560). The deduced polypeptide sequence had 138 amino acids, and was 100% similar to the reference sequence (AKA64754). The LvCTL3 had a molecular weight of 16.91 kDa and an isoelectric point (pI) of 4.66, while LvCTL4 had 15.75 and 4.58 kDa, respectively. The structure prediction results showed that LvCTL3 and LvCTL4 had one domain (CTLD), LvCTL3 had two α helices and nine β sheets, and LvCTL4 had two α helices and eight β sheets. Our results provide essential information for the heterologous expression and biosynthesis production of C-type lectins.

Engineering Amino Acid and Peptide Supramolecular Architectures through Fluorination.

Fluorinated non-natural amino acids are attracting considerable research interest, especially in the biomedical field and in materials science, thanks to their ability to self-assemble into peculiar supramolecular structures. The conformational changes induced by the presence of fluorine atoms obviously affect their functions, as well as the biological activity of the deriving peptides and proteins. Here, we will briefly describe the main effects of fluorination on the aggregation behavior of such building blocks, focusing in particular on their improved tendency to form fibrils, and gels therefrom. Our aim is to underline the promising potential of fluorination as a tool to affect the self-assembly features of amino acids, both when used alone and when inserted into polypeptide sequences. The ability of fluorine to influence physical, chemical, and structural properties of these substrates offers the possibility to engineer bioinspired materials with specific and tunable functions.

Unraveling the Photoionization Dynamics of Indole in Aqueous and Ethanol Solutions.

The photoionization dynamics of indole, the ultraviolet-B chromophore of tryptophan, were explored in water and ethanol using ultrafast transient absorption spectroscopy with 292, 268, and 200 nm excitation. By studying the femtosecond-to-nanosecond dynamics of indole in two different solvents, a new photophysical model has been generated that explains many previously unsolved facets of indole's complex solution phase photochemistry. Photoionization is only an active pathway for indole in aqueous solution, leading to a reduction in the fluorescence quantum yield in water-rich environments, which is frequently used in biophysical experiments as a key signature of the protein-folded state. Photoionization of indole in aqueous solution was observed for all three pump wavelengths but via two different mechanisms. For 200 nm excitation, electrons are ballistically ejected directly into the bulk solvent. Conversely, 292 and 268 nm excitation populates an admixture of two 1ππ* states, which form a dynamic equilibrium with a tightly bound indole cation and electron-ion pair. The ion pair dissociates on a nanosecond time scale, generating separated solvated electrons and indole cations. The charged species serve as important precursors to triplet indole production and greatly enhance the overall intersystem crossing rate. Our proposed photophysical model for indole in aqueous solution is the most appropriate for describing photoinduced dynamics of tryptophan in polypeptide sequences; tryptophan in aqueous pH 7 solution is zwitterionic, unlike in peptides, and resultantly has a competitive excited state proton transfer pathway that quenches the tryptophan fluorescence.

Expanding the molecular language of protein liquid-liquid phase separation.

Understanding the relationship between a polypeptide sequence and its phase separation has important implications for analysing cellular function, treating disease and designing novel biomaterials. Several sequence features have been identified as drivers for protein liquid-liquid phase separation (LLPS), schematized as a 'molecular grammar' for LLPS. Here we further probe how sequence modulates phase separation and the material properties of the resulting condensates, targeting sequence features previously overlooked in the literature. We generate sequence variants of a repeat polypeptide with either no charged residues, high net charge, no glycine residues or devoid of aromatic or arginine residues. All but one of 12 variants exhibited LLPS, albeit to different extents, despite substantial differences in composition. Furthermore, we find that all the condensates formed behaved like viscous fluids, despite large differences in their viscosities. Our results support the model of multiple interactions between diverse residue pairs-not just a handful of residues-working in tandem to drive the phase separation and dynamics of condensates.

Molecular mechanism analysis of apoptosis induced by silk fibroin peptides

Silk fibroin derived from silkworm cocoons exhibits excellent mechanical properties, good biocompatibility, and low immunogenicity. Previous studies showed that silk fibroin had an inhibitory effect on cells, suppressing proliferation and inducing apoptosis. However, the source of the toxicity and the mechanism of apoptosis induction are still unclear. In this study, we hypothesized that the toxicity of silk fibroin might originate from the crystalline region of the heavy chain of silk fibroin. We then verified the hypothesis and the specific induction mechanism. A target peptide segment was obtained from α-chymotrypsin. The potentially toxic mixture of silk fibroin peptides (SFPs) was separated by ion exchange, and the toxicity was tested by an MTT assay. The results showed that SFPs obtained after 4 h of enzymatic hydrolysis had significant cytotoxicity, and SFPs with isoelectric points of 4.0–6.8 (SFPα II) had a significant inhibitory effect on cell growth. LC-MS/MS analysis showed that SFPα II contained a large number of glycine-rich and alanine-rich repetitive sequence polypeptides from the heavy-chain crystallization region. A series of experiments showed that SFPα II mediated cell death through the apoptotic pathway by decreasing the expression of Bcl-2 protein and increasing the expression of Bax protein. SFPα II mainly affected the p53 pathway and the AMPK signaling pathway in HepG2 cells. SFPα II may indirectly increase the expression of Cers2 by inhibiting the phosphorylation of EGFR, which activated apoptotic signaling in the cellular mitochondrial pathway and inhibited the Akt/NF-κB pathway by increasing the expression of PPP2R2A.

Nanopore DNA sequencing technologies and their applications towards single-molecule proteomics.

Sequencing of nucleic acids with nanopores has emerged as a powerful tool offering rapid readout, high accuracy, low cost and portability. This label-free method for sequencing at the single-molecule level is an achievement on its own. However, nanopores also show promise for the technologically even more challenging sequencing of polypeptides, something that could considerably benefit biological discovery, clinical diagnostics and homeland security, as current techniques lack portability and speed. Here we survey the biochemical innovations underpinning commercial and academic nanopore DNA/RNA sequencing techniques, and explore how these advances can fuel developments in future protein sequencing with nanopores.

Molecular Dynamics Simulations of Polyelectrolyte Complexes.

Polyelectrolyte complexes (PECs) are currently of great interest due to their applications toward developing new adaptive materials and their relevance in membraneless organelles. These complexes emerge during phase separation when oppositely charged polymers are mixed in aqueous media. Peptide-based PECs are particularly useful toward developing new drug delivery methods due to their inherent biocompatibility. The underlying peptide sequence can be tuned to optimize specific material properties of the complex, such as interfacial tension and viscosity. Given their applicability, it would be advantageous to understand the underlying sequence-dependent phase behavior of oppositely charged peptides. Here, we report microsecond molecular dynamic simulations to characterize the effect of hydrophobicity on the sequence-dependent peptide conformation for model polypeptide sequences that were previously reported by Tabandeh et al. These sequences are designed with alternating chirality of the peptide backbone. We present microsecond simulations of six oppositely charged peptide pairs, characterizing the sequence-dependent effect on peptide size, degree of hydrogen bonding, secondary structure, and conformation. This analysis recapitulates sensible trends in peptide conformation and degree of hydrogen bonding, consistent with experimentally reported results. Ramachandran plots reveal that backbone conformation at the single amino acid level is highly influenced by the neighboring sequence in the chain. These results give insight into how subtle changes in hydrophobic side chain size and chirality influence the strength of hydrogen bonding between the chains and, ultimately, the secondary structure. Furthermore, principal component analysis reveals that the minimum energy structures may be subtly modulated by the underlying sequence.

Determinants that enable disordered protein assembly into discrete condensed phases.

Cells harbour numerous mesoscale membraneless compartments that house specific biochemical processes and perform distinct cellular functions. These protein- and RNA-rich bodies are thought to form through multivalent interactions among proteins and nucleic acids, resulting in demixing via liquid-liquid phase separation. Proteins harbouring intrinsically disordered regions (IDRs) predominate in membraneless organelles. However, it is not known whether IDR sequence alone can dictate the formation of distinct condensed phases. We identified a pair of IDRs capable of forming spatially distinct condensates when expressed in cells. When reconstituted in vitro, these model proteins do not co-partition, suggesting condensation specificity is encoded directly in the polypeptide sequences. Through computational modelling and mutagenesis, we identified the amino acids and chain properties governing homotypic and heterotypic interactions that direct selective condensation. These results form the basis of physicochemical principles that may direct subcellular organization of IDRs into specific condensates and reveal an IDR code that can guide construction of orthogonal membraneless compartments.

Experimental and Theoretical Mutation of Exciton States on the Smallest Type-I Photosynthetic Reaction Center Complex of a Green Sulfur Bacterium Chlorobaclum tepidum.

The exciton states on the smallest type-I photosynthetic reaction center complex of a green sulfur bacterium Chlorobaculum tepidum (GsbRC) consisting of 26 bacteriochlorophylls a (BChl a) and four chlorophylls a (Chl a) located on the homodimer of two PscA reaction center polypeptides were investigated. This analysis involved the study of exciton states through a combination of theoretical modeling and the genetic removal of BChl a pigments at eight sites. (1) A theoretical model of the pigment assembly exciton state on GsbRC was constructed using Poisson TrESP (P-TrESP) and charge density coupling (CDC) methods based on structural information. The model reproduced the experimentally obtained absorption spectrum, circular dichroism spectrum, and excitation transfer dynamics, as well as explained the effects of mutation. (2) Eight BChl a molecules at different locations on the GsbRC were selectively removed by genetic exchange of the His residue, which ligates the central Mg atom of BChl a, with the Leu residue on either one or two PscAs in the RC. His locations are conserved among all type-I RC plant polypeptide, cyanobacteria, and bacteria amino acid sequences. (3) Purified mutant-GsbRCs demonstrated distinct absorption and fluorescence spectra at 77 K, which were different from each other, suggesting successful pigment removal. (4) The same mutations were applied to the constructed theoretical model to analyze the outcomes of these mutations. (5) The combination of theoretical predictions and experimental mutations based on structural information is a new tool for studying the function and evolution of photosynthetic reaction centers.

Genome-Wide Identification and Expression Analyses of the FAR1/FHY3 Gene Family Provide Insight into Inflorescence Development in Maize.

As transcription factors derived from transposase, FAR-RED IMPAIRED RESPONSE1 (FAR1) and its homolog FHY3 play crucial roles in the regulation of light signaling and various stress responses by coordinating the expression of downstream target genes. Despite the extensive investigation of the FAR1/FHY3 family in Arabidopsis thaliana and other species, a comprehensive examination of these genes in maize has not been conducted thus far. In this study, we employed a genomic mining approach to identify 16 ZmFAR1 genes in the maize inbred line B73, which were further classified into five subgroups based on their phylogenetic relationships. The present study characterized the predicted polypeptide sequences, molecular weights, isoelectric points, chromosomal distribution, gene structure, conserved motifs, subcellular localizations, phylogenetic relationships, and cis-regulatory elements of all members belonging to the ZmFAR1 family. Furthermore, the tissue-specific expression of the 16 ZmFAR1 genes was analyzed using RNA-seq, and their expression patterns under far-red light conditions were validated in the ear and tassel through qRT-qPCR. The observed highly temporal and spatial expression patterns of these ZmFAR1 genes were likely associated with their specific functional capabilities under different light conditions. Further analysis revealed that six ZmFAR1 genes (ZmFAR1-1, ZmFAR1-10, ZmFAR1-11, ZmFAR1-12, ZmFAR1-14, and ZmFAR1-15) exhibited a response to simulated shading treatment and actively contributed to the development of maize ears. Through the integration of expression quantitative trait loci (eQTL) analyses and population genetics, we identified the presence of potential causal variations in ZmFAR1-14 and ZmFAR1-9, which play a crucial role in regulating the kernel row number and kernel volume weight, respectively. In summary, this study represents the initial identification and characterization of ZmFAR1 family members in maize, uncovering the functional variation in candidate regulatory genes associated with the improvement of significant agronomic traits during modern maize breeding.

Screening of Diabetes-Associated Autoantigens and Serum Antibody Profiles Using a Phage Display System.

Aims/Introduction: Phage display method is a crucial tool to find novel clinically valuable diabetes-associated autoantigens and identify known autoantigen epitopes that are associated with diabetes and could provide scientific support and guidance for the artificial construction and synthesis of Type I diabetes mellitus (T1DM) novel biomarkers. Materials and Methods: The phage display system was used for the "biopanning" of T1DM serum. Following the sequencing of the phage DNAs, the homologous sequences of the above fusion heptapeptide were further investigated by BLAST to track the origin of the polypeptide sequences. The antibody spectrum revealed new T1DM-associated epitopes and antibodies. Results: A total of 1200 phage DNA were sequenced and 9 conserved polypeptide sequences were collected. It was confirmed that the zinc transporter and islet amyloid protease were among them. The conserved polypeptide sequence 8 and another three distinctive polypeptide sequences derived from Proteus were discovered. Furthermore, we expressed recombinant proteins with homologous polypeptide sequences for the human islet amyloid polypeptide (IAPP) and polypeptide precursor human zinc transporter 8 (ZNT8). Through clinical sample detection for the serum from T1DM (n = 100) and T2DM (n = 200) patients, results demonstrate the importance and relevance of these polypeptides in the recognition and classification of various forms of diabetes. Conclusion: Human pancreatic and concurrent bacterial-derived protein antigens and their epitopes were identified in this research by the phage display system, which is crucial for distinguishing different types of diabetes.

Leucine rich-repeat sequence and the related protein in glioma

Leucine rich-repeat sequence (LRR sequence) is a special class of polypeptide sequences composed of several adjacent leucine residues. LRR sequence participates in evolution between species and across species. This sequence is widespread in a variety of proteins and has important biological functions. LRR protein plays a major part in the development of the nervous system and the maintenance of normal function. In addition, a large number of leucine repeats are closely related to the occurrence of a variety of diseases, such as leucine-rich repeat disease, leucine-rich peptide aggregate. Most importantly, it correlates with the development of brain tumors like glioma. This article is primarily focused on the structure and function of LRR sequence and the associated LRR proteins. Moreover, we summary the LRR-contain transmembrane proteins in nerve system and highlight the function of these proteins in glioma progression which takes the sequencing of LRR a potential personalized diagnosis and treatment of brain tumors.

A polypeptide derived from pilose antler ameliorates CUMS-induced depression-like behavior by SENP2-PLCβ4 signaling axis

Neurogenesis is known to be closely associated with depression. We aimed to investigate whether a polypeptide monomer derived from pilose antler (polypeptide sequence LSALEGVFYP, PAP) exerts an antidepressant effect by influencing neurogenesis, and to elucidate the mechanism of its antidepressant action. Behavioral tests were performed to observe the antidepressant effect of PAP. Neurogenesis in the dentate gyrus (DG) region of hippocampus was observed by immunofluorescence. The expression of key proteins of Sentrin/SUMO-specific proteases 2 (SENP2)- Phosphoinositide-specific phospholipase C beta 4 (PLCβ4) pathway was accessed by co-immunoprecipitation (Co-IP), and the calcium homeostasis associated proteins were observed via Western blot (WB). Subsequently, temozolomide (TMZ) pharmacologically blocked neurogenesis to verify the antidepressant effect of PAP on neurogenesis. The mechanism of PAP antidepressant effect was verified by constructing a sh-SENP2 virus vector to silence SENP2 protein. Finally, corticosterone (CORT)-induced PC12 cell model was used to verify whether PAP was involved in the process of deconjugated PLCβ4 SUMOylated. The results showed that PAP improved depression-like behavior and neurogenesis induced by chronic unpredictable mild stimulation (CUMS). In addition, PAP acted on SENP2-PLCβ4 pathway to deconjugate the SUMOylation of PLCβ4 and affect calcium homeostasis. Pharmacological blockade of neurogenesis by TMZ treatment impaired the antidepressant efficacy of PAP. Knockout of SENP2 in the CUMS model attenuated the antidepressant response of PAP, and the impaired neurogenesis was not ameliorated by PAP treatment. In summary, PAP acted on the SENP2-PLCβ4 signaling pathway to inhibit the SUMOylation of PLCβ4 and maintain calcium homeostasis, thereby protecting neurogenesis and playing an antidepressant role.

Occurrence and evolutionary conservation analysis of α-helical cationic amphiphilic segments in the human proteome.

The existence of encrypted fragments with antimicrobial activity in human proteins has been thoroughly demonstrated in the literature. Recently, algorithms for the large-scale identification of these segments in whole proteomes were developed, and the pervasiveness of this phenomenon was stated. These algorithms typically mine encrypted cationic and amphiphilic segments of proteins, which, when synthesized as individual polypeptide sequences, exert antimicrobial activity by membrane disruption. In the present report, the human reference proteome was submitted to the software kamal for the uncovering of protein segments that correspond to putative intragenic antimicrobial peptides (IAPs). The assessment of the identity of these segments, frequency, functional classes of parent proteins, structural relevance, and evolutionary conservation of amino acid residues within their corresponding proteins was conducted in silico. Additionally, the antimicrobial and anticancer activity of six selected synthetic peptides was evaluated. Our results indicate that cationic and amphiphilic segments can be found in 2% of all human proteins, but are more common in transmembrane and peripheral membrane proteins. These segments are surface-exposed basic patches whose amino acid residues present similar conservation scores to other residues with similar solvent accessibility. Moreover, the antimicrobial and anticancer activity of the synthetic putative IAP sequences was irrespective to whether these are associated to membranes in the cellular setting. Our study discusses these findings in light of the current understanding of encrypted peptide sequences, offering some insights into the relevance of these segments to the organism in the context of their harboring proteins or as separate polypeptide sequences.

Expression and characterization of an organic solvent tolerant recombinant lipase from Staphylococcus capitis SH6 for food wastewater treatment

The study illustrated here aims on an organic solvent tolerant lipase from Staphylococcus capitis (SCL). The gene part, encoding the mature lipase, was cloned and sequenced. The concluded polypeptide sequence, equivalent to the protein, consist of 388 amino acid residues with a molecular mass of about 45 kDa. A structure-based alignment of the SCL amino acid sequence shows high identities with those many staphylococcal lipases. From this alignment of sequences, the catalytic triad (Ser 117, Asp 308 and His 347) of SCL could be identified. The mature part of the SCL was expressed in Escherichia coli and the recombinant lipase (r-SCL) was purified to homogeneity. The purified r-SCL presented a quite interesting stability at low temperatures (< 30 °C) and the enzyme was found to be highly stable in polar organic solvent and at a pH ranging from 3 to 12. After that, we have demonstrated that the recombinant enzyme may be implicated in the biodegradability of oily wastewater from effluents of fast-food restaurants; the maximum conversion yield into fatty acids obtained at 30 °C, was 65%.

Pathologic polyglutamine aggregation begins with a self-poisoning polymer crystal.

A long-standing goal of amyloid research has been to characterize the structural basis of the rate-determining nucleating event. However, the ephemeral nature of nucleation has made this goal unachievable with existing biochemistry, structural biology, and computational approaches. Here, we addressed that limitation for polyglutamine (polyQ), a polypeptide sequence that causes Huntington's and other amyloid-associated neurodegenerative diseases when its length exceeds a characteristic threshold. To identify essential features of the polyQ amyloid nucleus, we used a direct intracellular reporter of self-association to quantify frequencies of amyloid appearance as a function of concentration, conformational templates, and rational polyQ sequence permutations. We found that nucleation of pathologically expanded polyQ involves segments of three glutamine (Q) residues at every other position. We demonstrate using molecular simulations that this pattern encodes a four-stranded steric zipper with interdigitated Q side chains. Once formed, the zipper poisoned its own growth by engaging naive polypeptides on orthogonal faces, in a fashion characteristic of polymer crystals with intramolecular nuclei. We further show that self-poisoning can be exploited to block amyloid formation, by genetically oligomerizing polyQ prior to nucleation. By uncovering the physical nature of the rate-limiting event for polyQ aggregation in cells, our findings elucidate the molecular etiology of polyQ diseases.