ci7b00640_si_001.pdf (2.87 MB)
Role of Molecular Interactions and Protein Rearrangement in the Dissociation Kinetics of p38α MAP Kinase Type-I/II/III Inhibitors
journal contribution
posted on 2018-04-05, 00:00 authored by Wanli You, Chia-en A. ChangUnderstanding
the governing factors of fast or slow inhibitor binding/unbinding
assists in developing drugs with preferred kinetic properties. For
inhibitors with the same binding affinity targeting different binding
sites of the same protein, the kinetic behavior can profoundly differ.
In this study, we investigated unbinding kinetics and mechanisms of
fast (type-I) and slow (type-II/III) binders of p38α mitogen-activated
protein kinase, where the crystal structures showed that type-I and
type-II/III inhibitors bind to pockets with different conformations
of the Asp-Phe-Gly (DFG) motif. The work used methods that combine
conventional molecular dynamics (MD), accelerated molecular dynamics
(AMD) simulations, and the newly developed pathway search guided by
internal motions (PSIM) method to find dissociation pathways. The
study focuses on revealing key interactions and molecular rearrangements
that hinder ligand dissociation by using umbrella sampling and post-MD
processing to examine changes in free energy during ligand unbinding.
As anticipated, the initial dissociation steps all require breaking
interactions that appeared in crystal structures of the bound complexes.
Interestingly, for type-I inhibitors such as SB2, p38α keeps
barrier-free conformational fluctuation in the ligand-bound complex
and during ligand dissociation. In contrast, with a type-II/III inhibitor
such as BIRB796, with the rearrangements of p38α in its bound
state, ligand unbinding features energetically unfavorable protein–ligand
concerted movement. Our results also show that the type-II/III inhibitors
preferred dissociation pathways through the allosteric channel, which
is consistent with an existing publication. The study suggests that
the level of required protein rearrangement is one major determining
factor of drug binding kinetics in p38α systems, providing useful
information for development of inhibitors.