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 3.3–4.8 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.
Highlights
Peptides mediate up to 40% of known protein-protein interactions in higher eukaryotes
Peptide docking with PeptiDock showed different levels of accuracy: root-mean-square deviations (RMSDs) of the peptide backbone compared with the bound X-ray structures were 3.3, 3.5, and 4.8 Å for the three peptides, respectively (Figures 1A–C and Table 1)
The first two were of acceptable quality predictions according to the Critical Assessment of PRediction of Interactions (CAPRI) peptide docking criteria (Janin et al, 2003), and the third one was slightly above acceptability cutoff
Summary
Peptides mediate up to 40% of known protein-protein interactions in higher eukaryotes. Peptides have served as promising drug candidates with high specificity and relatively low toxicity (Ahrens et al, 2012; Fosgerau and Hoffmann, 2015; Kahler et al, 2018; Lee et al, 2019). The number of peptide-based drugs being marketed is increasing in recent years (Ahrens et al, 2012; Fosgerau and Hoffmann, 2015; Kahler et al, 2018; Lee et al, 2019). Understanding the molecular mechanism of peptide-protein interactions is important in both basic biology and applied medical research
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