DPP3 MD and ASMD simulations

Utilizing computational studies, primarily involving molecular dynamics (MD) and adaptive steered molecular dynamics (ASMD) simulations, we investigate how catalytic inactivation of DPP3 influences the structural basis of its interaction with the Kelch domain. Specifically, our computational studies of both the wild type (WT) and E451A mutant of DPP3, in the presence and absence of the peptide inhibitor (IVYPW), have identified key structural differences between bound and unbound states, assessing their implications for Kelch domain binding. ASMD simulations provided insights into how DPP3 inactivation, either via mutation or peptidase inhibitor binding, affects the detachment of the ETGE-loop, a step considered rate-determining in the two-step Keap1-DPP3 binding mechanism.

Structures of DPP3—both ligand-free and with the IVYPW ligand bound in the active site of the WT and E451A mutant in its closed form—generated every 100 ns during a 1-microsecond-long standard MD simulation are provided in pdb format (without solvent). The input file used for productive MD simulation is also provided.

Structures of WT and E451A-mutated DPP3, in either closed (not additionally highlighted) or open (designated with an 'o' before the enzyme name) conformations, generated after each ASMD step as the structures closest to the Jarzynski average using a pulling speed of 0.5 Å/ns are provided. In addition to the ligand-free structures, structures of the complexes with IVYPW are also included.

An example of the input file used for ASMD simulations at each phase of the DPP3 structure, along with the corresponding restraint files for each phase, is provided.