Improved Modeling of Peptide-Protein Binding Through Global Docking and Accelerated Molecular Dynamics Simulations
Peptides mediate up to 40% of known protein-protein interactions in higher eukaryotes and play a key role in cellular signaling, protein trafficking, immunology, and oncology. However, it is challenging to predict peptide-protein binding with conventional computational modeling approaches, due to sl...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2019-10-01
|
| Series: | Frontiers in Molecular Biosciences |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fmolb.2019.00112/full |
| _version_ | 1818695873968734208 |
|---|---|
| author | Jinan Wang Andrey Alekseenko Andrey Alekseenko Dima Kozakov Dima Kozakov Yinglong Miao |
| author_facet | Jinan Wang Andrey Alekseenko Andrey Alekseenko Dima Kozakov Dima Kozakov Yinglong Miao |
| author_sort | Jinan Wang |
| collection | DOAJ |
| description | Peptides mediate up to 40% of known protein-protein interactions in higher eukaryotes and play a key role in cellular signaling, protein trafficking, immunology, and oncology. However, it is challenging to predict peptide-protein binding with conventional computational modeling approaches, due to slow dynamics and high peptide flexibility. Here, we present a prototype of the approach which combines global peptide docking using ClusPro PeptiDock and all-atom enhanced simulations using Gaussian accelerated molecular dynamics (GaMD). For three distinct model peptides, the lowest backbone root-mean-square deviations (RMSDs) of their bound conformations relative to X-ray structures obtained from PeptiDock were 3.3–4.8 Å, being medium quality predictions according to the Critical Assessment of PRediction of Interactions (CAPRI) criteria. GaMD simulations refined the peptide-protein complex structures with significantly reduced peptide backbone RMSDs of 0.6–2.7 Å, yielding two high quality (sub-angstrom) and one medium quality models. Furthermore, the GaMD simulations identified important low-energy conformational states and revealed the mechanism of peptide binding to the target proteins. Therefore, PeptiDock+GaMD is a promising approach for exploring peptide-protein interactions. |
| first_indexed | 2024-12-17T13:52:24Z |
| format | Article |
| id | doaj.art-9e3aed3fe42d4f378ab6d23c520bb47a |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-12-17T13:52:24Z |
| publishDate | 2019-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-9e3aed3fe42d4f378ab6d23c520bb47a2022-12-21T21:46:01ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2019-10-01610.3389/fmolb.2019.00112486588Improved Modeling of Peptide-Protein Binding Through Global Docking and Accelerated Molecular Dynamics SimulationsJinan Wang0Andrey Alekseenko1Andrey Alekseenko2Dima Kozakov3Dima Kozakov4Yinglong Miao5Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS, United StatesLaufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY, United StatesDepartment of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, United StatesLaufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY, United StatesDepartment of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, United StatesCenter for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS, United StatesPeptides mediate up to 40% of known protein-protein interactions in higher eukaryotes and play a key role in cellular signaling, protein trafficking, immunology, and oncology. However, it is challenging to predict peptide-protein binding with conventional computational modeling approaches, due to slow dynamics and high peptide flexibility. Here, we present a prototype of the approach which combines global peptide docking using ClusPro PeptiDock and all-atom enhanced simulations using Gaussian accelerated molecular dynamics (GaMD). For three distinct model peptides, the lowest backbone root-mean-square deviations (RMSDs) of their bound conformations relative to X-ray structures obtained from PeptiDock were 3.3–4.8 Å, being medium quality predictions according to the Critical Assessment of PRediction of Interactions (CAPRI) criteria. GaMD simulations refined the peptide-protein complex structures with significantly reduced peptide backbone RMSDs of 0.6–2.7 Å, yielding two high quality (sub-angstrom) and one medium quality models. Furthermore, the GaMD simulations identified important low-energy conformational states and revealed the mechanism of peptide binding to the target proteins. Therefore, PeptiDock+GaMD is a promising approach for exploring peptide-protein interactions.https://www.frontiersin.org/article/10.3389/fmolb.2019.00112/fullpeptide-protein bindingpeptide dockingPeptiDockgaussian accelerated molecular dynamics (GaMD)peptide flexibility |
| spellingShingle | Jinan Wang Andrey Alekseenko Andrey Alekseenko Dima Kozakov Dima Kozakov Yinglong Miao Improved Modeling of Peptide-Protein Binding Through Global Docking and Accelerated Molecular Dynamics Simulations Frontiers in Molecular Biosciences peptide-protein binding peptide docking PeptiDock gaussian accelerated molecular dynamics (GaMD) peptide flexibility |
| title | Improved Modeling of Peptide-Protein Binding Through Global Docking and Accelerated Molecular Dynamics Simulations |
| title_full | Improved Modeling of Peptide-Protein Binding Through Global Docking and Accelerated Molecular Dynamics Simulations |
| title_fullStr | Improved Modeling of Peptide-Protein Binding Through Global Docking and Accelerated Molecular Dynamics Simulations |
| title_full_unstemmed | Improved Modeling of Peptide-Protein Binding Through Global Docking and Accelerated Molecular Dynamics Simulations |
| title_short | Improved Modeling of Peptide-Protein Binding Through Global Docking and Accelerated Molecular Dynamics Simulations |
| title_sort | improved modeling of peptide protein binding through global docking and accelerated molecular dynamics simulations |
| topic | peptide-protein binding peptide docking PeptiDock gaussian accelerated molecular dynamics (GaMD) peptide flexibility |
| url | https://www.frontiersin.org/article/10.3389/fmolb.2019.00112/full |
| work_keys_str_mv | AT jinanwang improvedmodelingofpeptideproteinbindingthroughglobaldockingandacceleratedmoleculardynamicssimulations AT andreyalekseenko improvedmodelingofpeptideproteinbindingthroughglobaldockingandacceleratedmoleculardynamicssimulations AT andreyalekseenko improvedmodelingofpeptideproteinbindingthroughglobaldockingandacceleratedmoleculardynamicssimulations AT dimakozakov improvedmodelingofpeptideproteinbindingthroughglobaldockingandacceleratedmoleculardynamicssimulations AT dimakozakov improvedmodelingofpeptideproteinbindingthroughglobaldockingandacceleratedmoleculardynamicssimulations AT yinglongmiao improvedmodelingofpeptideproteinbindingthroughglobaldockingandacceleratedmoleculardynamicssimulations |