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bioRxiv · 10.1101/743773

Improved Modeling of Peptide-Protein Binding through Global Docking and Accelerated Molecular Dynamics Simulations

Wang, j.·Alekseenko, A.·Kozakov, D.·Miao, Y.
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Abstract

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 [A] - 4.8 [A], 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 [A] - 2.7 [A], 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.

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Wang, j., Alekseenko, A., Kozakov, D., Miao, Y.. 2019-08-24. Improved Modeling of Peptide-Protein Binding through Global Docking and Accelerated Molecular Dynamics Simulations. https://doi.org/10.1101/743773

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