title: Conformational preference of ChaK1 binding peptides: a molecular dynamics study.
abstract: TRPM7/ChaK1 is a recently discovered atypical protein kinase that has been suggested to selectively phosphorylate the substrate residues located in alpha-helices. However, the actual structure of kinase-substrate complex has not been determined experimentally and the recognition mechanism remains unknown. In this work we explored possible kinase-substrate binding modes and the likelihood of an alpha-helix docking interaction, within a kinase active site, using molecular modeling. Specifically kinase ChaK1 and its two peptide substrates were examined; one was an 11-residue segment from the N-terminal domain of annexin-1, a putative endogenous substrate for ChaK1, and the other was an engineered 16-mer peptide substrate determined via peptide library screening. Simulated annealing (SA), replica-exchange molecular dynamics (REMD) and steered molecular dynamics (SMD) simulations were performed on the two peptide substrates and the ChaK1-substrate complex in solution. The simulations indicate that the two substrate peptides are unlikely to bind and react with the ChaK1 kinase in a stable alpha-helical conformation overall. The key structural elements, sequence motifs, and amino acid residues in the ChaK1 and their possible functions involved in the substrate recognition are discussed.PACS Codes: 87.15.A-
authors.affiliation: Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA. pren@mail.utexas.edu.
authors.forename: Jiajing
authors.initials: J
authors.lastname: Zhang
authors.forename: Christopher A
authors.initials: CA
authors.lastname: King
authors.forename: Kevin
authors.initials: K
authors.lastname: Dalby
authors.forename: Pengyu
authors.initials: P
authors.lastname: Ren