ArticleJournal of biomolecular structure & dynamics2018
An unexpected switch in peptide binding mode: from simulation to substrate specificity.
Article in Journal of biomolecular structure & dynamics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 12 citations in OpenAlex.
- Drug Discovery Strategies for Kallikrein-Related Peptidases.International journal of molecular sciences · 2025Review
- A Computational Perspective to Intermolecular Interactions and the Role of the Solvent on Regulating Protein Properties.Chemical reviews · 2025Review
- Efficient Refinement of Complex Structures of Flexible Histone Peptides Using Post-Docking Molecular Dynamics Protocols.International journal of molecular sciences · 2024Article
- Peptide Gaussian accelerated molecular dynamics (Pep-GaMD): Enhanced sampling and free energy and kinetics calculations of peptide binding.The Journal of chemical physics · 2020Article
- Improved Modeling of Peptide-Protein Binding Through Global Docking and Accelerated Molecular Dynamics Simulations.Frontiers in molecular biosciences · 2019Article
- Gaussian accelerated molecular dynamics (GaMD): principles and applications.Wiley interdisciplinary reviews. Computational molecular scienceArticle
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
A ten microsecond molecular dynamics simulation of a kallikrein-related peptidase 7 peptide complex revealed an unexpected change in binding mode. After more than two microseconds unrestrained sampling we observe a spontaneous transition of the binding pose including a 180° rotation around the P1 residue. Subsequently, the substrate peptide occupies the prime side region rather than the cognate non-prime side in a stable conformation. We characterize the unexpected binding mode in terms of contacts, solvent-accessible surface area, molecular interactions and energetic properties. We compare the new pose to inhibitor-bound structures of kallikreins with occupied prime side and find that a similar orientation is adopted. Finally, we apply in silico mutagenesis based on the alternative peptide binding position to explore the prime side specificity of kallikrein-related peptidase 7 and compare it to available experimental data. Our study provides the first microsecond time scale simulation data on a kallikrein protease and shows previously unexplored prime side interactions. Therefore, we expect our study to advance the rational design of inhibitors targeting kallikrein-related peptidase 7, an emerging drug target involved in several skin diseases as well as cancer.
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Registered trials
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