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

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 peptid

SUBMITTER: Kahler U 

PROVIDER: S-EPMC6334781 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature