title: Binding free energy landscape of domain-peptide interactions.
abstract: Peptide recognition domains (PRDs) are ubiquitous protein domains which mediate large numbers of protein interactions in the cell. How these PRDs are able to recognize peptide sequences in a rapid and specific manner is incompletely understood. We explore the peptide binding process of PDZ domains, a large PRD family, from an equilibrium perspective using an all-atom Monte Carlo (MC) approach. Our focus is two different PDZ domains representing two major PDZ classes, I and II. For both domains, a binding free energy surface with a strong bias toward the native bound state is found. Moreover, both domains exhibit a binding process in which the peptides are mostly either bound at the PDZ binding pocket or else interact little with the domain surface. Consistent with this, various binding observables show a temperature dependence well described by a simple two-state model. We also find important differences in the details between the two domains. While both domains exhibit well-defined binding free energy barriers, the class I barrier is significantly weaker than the one for class II. To probe this issue further, we apply our method to a PDZ domain with dual specificity for class I and II peptides, and find an analogous difference in their binding free energy barriers. Lastly, we perform a large number of fixed-temperature MC kinetics trajectories under binding conditions. These trajectories reveal significantly slower binding dynamics for the class II domain relative to class I. Our combined results are consistent with a binding mechanism in which the peptide C terminal residue binds in an initial, rate-limiting step.
authors.affiliation: Department of Astronomy and Theoretical Physics, Computational Biology and Biological Physics Group, Lund University, Lund, Sweden.
authors.forename: Iskra
authors.initials: I
authors.lastname: Staneva
authors.forename: Stefan
authors.initials: S
authors.lastname: Wallin
mesh_terms: D003198:Computer Simulation; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D009010:Monte Carlo Method; D054731:PDZ Domains; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D013816:Thermodynamics
chemical_list: D010455:Peptides; C050632:polypeptide C