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| Autori principali: | , , , , , |
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| Natura: | Artículo científico |
| Lingua: | en |
| Pubblicazione: |
Food research international (Ottawa, Ont.)
2024
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| Soggetti: | |
| Accesso online: | https://pubmed.ncbi.nlm.nih.gov/39577955/ |
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| _version_ | 1868266277672321024 |
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| author | Ouyang, Yuhong Yue, Yang Wu, Ning Wang, Jing Geng, Lihua Zhang, Quanbin |
| author_facet | Ouyang, Yuhong Yue, Yang Wu, Ning Wang, Jing Geng, Lihua Zhang, Quanbin Ouyang, Yuhong Yue, Yang Wu, Ning Wang, Jing Geng, Lihua Zhang, Quanbin |
| collection | PubMed - marine biology |
| contents | Identification and anticoagulant mechanisms of novel factor XIa inhibitory peptides by virtual screening of a in silico generated deep-sea peptide database. Ouyang, Yuhong Yue, Yang Wu, Ning Wang, Jing Geng, Lihua Zhang, Quanbin Factor XIa Anticoagulants Peptides Molecular Docking Simulation Molecular Dynamics Simulation Animals Partial Thromboplastin Time Blood Coagulation Computer Simulation Thrombin Time Humans Amino Acid Sequence Hydrogen Bonding The objective of this study was to identify novel anticoagulant peptides from the deep-sea using multiple in silico methods, and to investigate their inhibitory activity and molecular mechanisms. A deep-sea peptide database was firstly constructed by performing virtual proteolysis on protein sequences from animals inhabiting deep-sea hydrothermal vents and cold seeps. Candidate anticoagulant peptides were identified through molecular docking and binding free energy screening against FXIa as the target. Two novel anticoagulant peptides, PRNIF (IC = 0.67 mM) and GNDRCL (IC = 1.52 mM), were identified, and their anticoagulant activities were verified in vitro. PRNIF was demonstrated to be a noncompetitive inhibitor of FXIa, and caused significant prolongation of thrombin time (TT) and activated partial thromboplastin time (APTT), whereas GNDRCL markedly prolonged the APTT only. Molecular dynamics simulations demonstrated considerable conformational shifts of both anticoagulant peptides when bound to the active sites of FXIa. The lowest energy binding poses of the FXIa-peptide complexes for PRNIF and GNDRCL exhibited comparable numbers of hydrogen bonds and binding free energies. However, occupancy analysis revealed completely distinct stability characteristics of the hydrogen bond interactions. The conserved residue Asp569 in the S1 pocket of FXIa formed strong and stable hydrogen bonds as well as a salt bridge with the arginine residues of PRNIF, which were not observed in the FXIa-GNDRCL complex. To our knowledge, PRNIF represented the first FXIa inhibitory peptide derived from the deep-sea, which may contribute to the development and utilization of deep-sea peptides resources. Two deep-sea peptides may potentially serve as an alternative food-derived ingredient that could be utilized for thrombosis prevention. |
| format | Artículo científico |
| id | pubmed_39577955 |
| institution | PubMed |
| language | en |
| publishDate | 2024 |
| publisher | Food research international (Ottawa, Ont.) |
| record_format | pubmed |
| spellingShingle | Identification and anticoagulant mechanisms of novel factor XIa inhibitory peptides by virtual screening of a in silico generated deep-sea peptide database. Ouyang, Yuhong Yue, Yang Wu, Ning Wang, Jing Geng, Lihua Zhang, Quanbin Factor XIa Anticoagulants Peptides Molecular Docking Simulation Molecular Dynamics Simulation Animals Partial Thromboplastin Time Blood Coagulation Computer Simulation Thrombin Time Humans Amino Acid Sequence Hydrogen Bonding Identification and anticoagulant mechanisms of novel factor XIa inhibitory peptides by virtual screening of a in silico generated deep-sea peptide database. Ouyang, Yuhong Yue, Yang Wu, Ning Wang, Jing Geng, Lihua Zhang, Quanbin Factor XIa Anticoagulants Peptides Molecular Docking Simulation Molecular Dynamics Simulation Animals Partial Thromboplastin Time Blood Coagulation Computer Simulation Thrombin Time Humans Amino Acid Sequence Hydrogen Bonding The objective of this study was to identify novel anticoagulant peptides from the deep-sea using multiple in silico methods, and to investigate their inhibitory activity and molecular mechanisms. A deep-sea peptide database was firstly constructed by performing virtual proteolysis on protein sequences from animals inhabiting deep-sea hydrothermal vents and cold seeps. Candidate anticoagulant peptides were identified through molecular docking and binding free energy screening against FXIa as the target. Two novel anticoagulant peptides, PRNIF (IC = 0.67 mM) and GNDRCL (IC = 1.52 mM), were identified, and their anticoagulant activities were verified in vitro. PRNIF was demonstrated to be a noncompetitive inhibitor of FXIa, and caused significant prolongation of thrombin time (TT) and activated partial thromboplastin time (APTT), whereas GNDRCL markedly prolonged the APTT only. Molecular dynamics simulations demonstrated considerable conformational shifts of both anticoagulant peptides when bound to the active sites of FXIa. The lowest energy binding poses of the FXIa-peptide complexes for PRNIF and GNDRCL exhibited comparable numbers of hydrogen bonds and binding free energies. However, occupancy analysis revealed completely distinct stability characteristics of the hydrogen bond interactions. The conserved residue Asp569 in the S1 pocket of FXIa formed strong and stable hydrogen bonds as well as a salt bridge with the arginine residues of PRNIF, which were not observed in the FXIa-GNDRCL complex. To our knowledge, PRNIF represented the first FXIa inhibitory peptide derived from the deep-sea, which may contribute to the development and utilization of deep-sea peptides resources. Two deep-sea peptides may potentially serve as an alternative food-derived ingredient that could be utilized for thrombosis prevention. |
| title | Identification and anticoagulant mechanisms of novel factor XIa inhibitory peptides by virtual screening of a in silico generated deep-sea peptide database. |
| topic | Factor XIa Anticoagulants Peptides Molecular Docking Simulation Molecular Dynamics Simulation Animals Partial Thromboplastin Time Blood Coagulation Computer Simulation Thrombin Time Humans Amino Acid Sequence Hydrogen Bonding |
| url | https://pubmed.ncbi.nlm.nih.gov/39577955/ |