The Glycine-Rich Region as a Flexible Molecular Glue Promoting hPrP106–145 Aggregation into β-Sheet Structures
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2025
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| _version_ | 1866901678887796736 |
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| author | Zhang, Xiaohan Xu, Huan Tang, Huayuan Lv, Zhongyue Zou, Yu Huang, Fengjuan Ding, Feng Sun, Yunxiang |
| author_facet | Zhang, Xiaohan Xu, Huan Tang, Huayuan Lv, Zhongyue Zou, Yu Huang, Fengjuan Ding, Feng Sun, Yunxiang |
| contents | <p><span>The abnormal aggregation of human prion protein (hPrP) into cross-β fibrillar amyloid deposits is associated with prion diseases such as Creutzfeldt-Jakob disease and fatal familial insomnia. However, the molecular mechanisms underlying the early stages of prion aggregation remain poorly understood. In this study, we employed multiple long-timescale atomistic discrete molecular dynamics (DMD) simulations to investigate the conformational dynamics of hPrP<sub>106–145</sub>, a critical fragment with intrinsic aggregation propensity and key involvement in infectivity. Our results revealed that the hPrP<sub>106–145</sub> monomer primarily adopted a helical conformation in the alanine-rich region (residues 109–116), while the remaining sequence was largely unstructured, exhibiting dynamic β-sheet formation around residues <sup>120</sup>AVV<sup>122</sup>, <sup>128</sup>YVL<sup>130</sup>, and <sup>138</sup>IIH<sup>140</sup>. Upon dimerization, β-sheet formation was significantly enhanced, particularly around <sup>138</sup>IIH<sup>140</sup>, which displayed the highest β-sheet propensity and inter-peptide contact frequency, underscoring its pivotal role in aggregate stabilization. The glycine-rich region (residues 119–131) was found to facilitate aggregation by conferring structural flexibility due to glycine’s minimal steric hindrance. This flexibility allowed hydrophobic and aromatic residues to collapse dynamically, forming transient intra- and inter-peptide β-sheets. These interactions acted as a molecular glue, promoting aggregation while maintaining structural adaptability. Although β-sheet formation lowered potential energy, excessive β-sheet content resulted in significant entropic loss, highlighting a trade-off between stability and conformational entropy. Overall, this study provides molecular insights into the early nucleation events of hPrP<sub>106–145</sub> aggregation, emphasizing the critical role of glycine-mediated flexibility. Our findings deepen the understanding of prion misfolding and offer a computational framework for exploring glycine-rich peptide phase separation in amyloid-related disorders.</span></p> |
| format | Recurso digital |
| id | zenodo_https___doi_org_10_5281_zenodo_15129228 |
| institution | Zenodo |
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| publishDate | 2025 |
| publisher | Zenodo |
| record_format | zenodo |
| spellingShingle | The Glycine-Rich Region as a Flexible Molecular Glue Promoting hPrP106–145 Aggregation into β-Sheet Structures Zhang, Xiaohan Xu, Huan Tang, Huayuan Lv, Zhongyue Zou, Yu Huang, Fengjuan Ding, Feng Sun, Yunxiang <p><span>The abnormal aggregation of human prion protein (hPrP) into cross-β fibrillar amyloid deposits is associated with prion diseases such as Creutzfeldt-Jakob disease and fatal familial insomnia. However, the molecular mechanisms underlying the early stages of prion aggregation remain poorly understood. In this study, we employed multiple long-timescale atomistic discrete molecular dynamics (DMD) simulations to investigate the conformational dynamics of hPrP<sub>106–145</sub>, a critical fragment with intrinsic aggregation propensity and key involvement in infectivity. Our results revealed that the hPrP<sub>106–145</sub> monomer primarily adopted a helical conformation in the alanine-rich region (residues 109–116), while the remaining sequence was largely unstructured, exhibiting dynamic β-sheet formation around residues <sup>120</sup>AVV<sup>122</sup>, <sup>128</sup>YVL<sup>130</sup>, and <sup>138</sup>IIH<sup>140</sup>. Upon dimerization, β-sheet formation was significantly enhanced, particularly around <sup>138</sup>IIH<sup>140</sup>, which displayed the highest β-sheet propensity and inter-peptide contact frequency, underscoring its pivotal role in aggregate stabilization. The glycine-rich region (residues 119–131) was found to facilitate aggregation by conferring structural flexibility due to glycine’s minimal steric hindrance. This flexibility allowed hydrophobic and aromatic residues to collapse dynamically, forming transient intra- and inter-peptide β-sheets. These interactions acted as a molecular glue, promoting aggregation while maintaining structural adaptability. Although β-sheet formation lowered potential energy, excessive β-sheet content resulted in significant entropic loss, highlighting a trade-off between stability and conformational entropy. Overall, this study provides molecular insights into the early nucleation events of hPrP<sub>106–145</sub> aggregation, emphasizing the critical role of glycine-mediated flexibility. Our findings deepen the understanding of prion misfolding and offer a computational framework for exploring glycine-rich peptide phase separation in amyloid-related disorders.</span></p> |
| title | The Glycine-Rich Region as a Flexible Molecular Glue Promoting hPrP106–145 Aggregation into β-Sheet Structures |
| url | https://doi.org/10.5281/zenodo.15129228 |