| http://purl.uniprot.org/citations/25207671 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/25207671 | http://www.w3.org/2000/01/rdf-schema#comment | "Intrinsically disordered proteins (IDPs) often rely on electrostatic interactions to bind their structured targets. To obtain insight into the mechanism of formation of the electrostatic encounter complex, we investigated the binding of the peptide Sos (PPPVPPRRRR), which serves as a minimal model for an IDP, to the c-Crk N-terminal SH3 domain. Initially, we measured ¹⁵N relaxation rates at two magnetic field strengths and determined the binding shifts for the complex of Sos with wild-type SH3. We have also recorded a 3 μs molecular dynamics (MD) trajectory of this complex using the Amber ff99SB*-ILDN force field. The comparison of the experimental and simulated data shows that MD simulation consistently overestimates the strength of salt bridge interactions at the binding interface. The series of simulations using other advanced force fields also failed to produce any satisfactory results. To address this issue, we have devised an empirical correction to the Amber ff99SB*-ILDN force field whereby the Lennard-Jones equilibrium distance for the nitrogen-oxygen pair across the Arg-to-Asp and Arg-to-Glu salt bridges has been increased by 3%. Implementing this correction resulted in a good agreement between the simulations and the experiment. Adjusting the strength of salt bridge interactions removed a certain amount of strain contained in the original MD model, thus improving the binding of the hydrophobic N-terminal portion of the peptide. The arginine-rich C-terminal portion of the peptide, freed from the effect of the overstabilized salt bridges, was found to interconvert more rapidly between its multiple conformational states. The modified MD protocol has also been successfully used to simulate the entire binding process. In doing so, the peptide was initially placed high above the protein surface. It then arrived at the correct bound pose within ∼2 Å of the crystallographic coordinates. This simulation allowed us to analyze the details of the dynamic binding intermediate, i.e., the electrostatic encounter complex. However, an experimental characterization of this transient, weakly populated state remains out of reach. To overcome this problem, we designed the double mutant of c-Crk N-SH3 in which mutations Y186L and W169F abrogate tight Sos binding and shift the equilibrium toward the intermediate state resembling the electrostatic encounter complex. The results of the combined NMR and MD study of this engineered system will be reported in the next part of this paper."xsd:string |
| http://purl.uniprot.org/citations/25207671 | http://purl.org/dc/terms/identifier | "doi:10.1021/bi500904f"xsd:string |
| http://purl.uniprot.org/citations/25207671 | http://purl.uniprot.org/core/author | "Xue Y."xsd:string |
| http://purl.uniprot.org/citations/25207671 | http://purl.uniprot.org/core/author | "Zhu F."xsd:string |
| http://purl.uniprot.org/citations/25207671 | http://purl.uniprot.org/core/author | "Skrynnikov N.R."xsd:string |
| http://purl.uniprot.org/citations/25207671 | http://purl.uniprot.org/core/author | "Yuwen T."xsd:string |
| http://purl.uniprot.org/citations/25207671 | http://purl.uniprot.org/core/date | "2014"xsd:gYear |
| http://purl.uniprot.org/citations/25207671 | http://purl.uniprot.org/core/name | "Biochemistry"xsd:string |
| http://purl.uniprot.org/citations/25207671 | http://purl.uniprot.org/core/pages | "6473-6495"xsd:string |
| http://purl.uniprot.org/citations/25207671 | http://purl.uniprot.org/core/title | "Role of electrostatic interactions in binding of peptides and intrinsically disordered proteins to their folded targets. 1. NMR and MD characterization of the complex between the c-Crk N-SH3 domain and the peptide Sos."xsd:string |
| http://purl.uniprot.org/citations/25207671 | http://purl.uniprot.org/core/volume | "53"xsd:string |
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