Computed Binding of Peptides to Proteins with MELD-Accelerated Molecular Dynamics

It
has been a challenge to compute the poses and affinities for
binding of peptides to proteins by molecular dynamics (MD) simulations.
Such computations would be valuable for capturing the physics and
the conformational freedom of the molecules, but they are currently
too computationally expensive. Here we describe using MELD (Modeling
Employing Limited Data)-accelerated MD for finding the binding poses
and approximate relative binding free energies for flexible-peptide/protein
interactions. MELD uses only weak information about the binding motif
and not the detailed binding mode that is typically required by other
free-energy-based methods. We apply this technique to study binding
of P53-derived peptides to MDM2 and MDMX. We find that MELD finds
correct poses, that the binding induces the peptide into the correct
helical conformation, and that it is capable of roughly estimating
relative binding affinities. This method may be useful in peptide
drug discovery.