An unexpected switch in peptide binding mode: from simulation to substrate specificity

Kahler, Ursula; Fuchs, Julian E.; Goettig, Peter; Liedl, Klaus R.

doi:10.1080/07391102.2017.1407674

Cited by 8 publications

(13 citation statements)

References 77 publications

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“…Peptide binding plays a key role in cellular signaling, protein trafficking, immune response, and oncology (Petsalaki and Russell, 2008; Das et al, 2013). In addition, 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).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, 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). Therefore, understanding the molecular mechanism of peptide-protein interactions is important in both basic biology and applied medical research.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Alekseenko

Kozakov

et al. 2019

Front. Mol. Biosci.

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Wang

Alekseenko

Kozakov

et al. 2019

Front. Mol. Biosci.

View full text Add to dashboard Cite

show abstract

“…Peptide binding plays a key role in cellular signaling, protein trafficking, immune response and oncology (Petsalaki and Russell, 2008;Das et al, 2013). In addition, 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 peptidebased drugs being marketed is increasing in recent years (Ahrens et al, 2012;Fosgerau and Hoffmann, 2015;Kahler et al, 2018;Lee et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, 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 peptidebased drugs being marketed is increasing in recent years (Ahrens et al, 2012;Fosgerau and Hoffmann, 2015;Kahler et al, 2018;Lee et al, 2019). Therefore, understanding the molecular mechanism of peptide-protein interactions is important in both basic biology and applied medical research.…”

Section: Introductionmentioning

confidence: 99%

“…Molecular dynamics (MD) is a powerful technique that enables all-atom simulations of biomolecules. MD simulations are able to fully account for the flexibility of peptides and proteins during their binding Wan et al, 2015;Salmaso et al, 2017;Yadahalli et al, 2017;Kahler et al, 2018). MD has been used to refine binding poses of peptides in proteins in the pepATTRACT (de Vries et al, 2017) and AnchorDock(Ben-Shimon and Niv, 2015) docking protocols.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Alekseenko

Kozakov

et al. 2019

Preprint

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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 Å -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 Å -2.7 Å, yielding two high quality (subangstrom) 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 peptideprotein interactions.

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Inhibition constant and stability of tripeptide inhibitors of gut trypsin‐like enzyme of the soybean pest Anticarsia gemmatalis

Barros

Meriño‐Cabrera

Castro

et al. 2022

Arch Insect Biochem Physiol

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Insects overcome the action of natural protease inhibitors (PIs) due to evolutionary adaptations through endogenous proteolysis and reprogramming proteases. Insect adaptations complicate the formulation of IP‐based crop protection products. However, small peptides designed based on the active site of enzymes have shown promising results that could change this scenario. GORE1 and GORE2 are designed tripeptides that reduce the survival of Anticarsia gemmatalis when ingested orally. In this article, the stability and ability of the peptides to bind trypsin‐like enzymes of A. gemmatalis were evaluated by molecular dynamics (MD) simulations. The ability of the peptides to inhibit trypsin‐like enzymes in vivo was compared with the SKTI protein by feeding A. gemmatalis larvae at different concentrations, followed by an inhibition persistence assay. During the MD simulation of enzyme–ligand complexes, both peptides showed a small variation of root‐mean‐square deviation and root‐mean‐square fluctuation, suggesting that these molecules reach equilibrium when forming a complex with the trypsin‐like enzyme. Furthermore, both peptides form hydrogen bonds with substrate recognition sites of A. gemmatalis trypsin‐like enzyme, with GORE2 having more interactions than GORE1. Larvae of A. gemmatalis exposed to the peptides and SKTI showed a similar reduction in proteolytic activity, but the persistence of inhibition of trypsin‐like enzyme was longer in peptide‐fed insects. Despite their size, the peptides exhibit important active and substrate binding site interactions, stability during complex formation, and steadiness effects in vivo. The results provide fundamental information for the development of mimetic molecules and help in decision‐making for the selection of delivery methods for larger‐scale experiments regarding similar molecules.

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An unexpected switch in peptide binding mode: from simulation to substrate specificity

Cited by 8 publications

References 77 publications

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

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

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

Inhibition constant and stability of tripeptide inhibitors of gut trypsin‐like enzyme of the soybean pest Anticarsia gemmatalis

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