TCB Publications - Abstract
Shashank Pant and Emad Tajkhorshid. Microscopic characterization of GRP1 PH domain interaction with anionic membranes. Journal of Computational Chemistry, 41:489-499, 2020. (PMC: PMC7000246)
), and acts as a second
messenger. Using an extensive array of molecular dynamics (MD) simulations employing highly
mobile membrane mimetic (HMMM) model as well as complementary full membrane simulations we
capture differentiable binding and dynamics of GRP1-PHD in the presence of membranes containing
PC, PS and PIP lipids in varying compositions. While GRP1-PHD forms only transient
interactions with pure PC membranes, incorporation of anionic lipids resulted in stable membrane-
bound configurations. We report the first observation of two distinct PIP binding modes on
GRP1-PHD, involving PIP interactions at a "canonical" and at an "alternate" site, suggesting the
possibility of simultaneous binding of multiple anionic lipids. The full membrane simulations
confirmed the stability of the membrane bound pose of GRP1-PHD as captured from our HMMM
membrane binding simulations. By performing additional steered membrane unbinding simulations
and calculating non equilibrium work associated with the process, as well as metadynamics
simulations, on the protein bound to full membranes, allowing for more quantitative examination of
the binding strength of the GRP1-PHD to the membrane, we demonstrate that along with the bound
PIP, surrounding anionic PS lipids increase the energetic cost of unbinding of GRP1-PHD from
the canonical mode, causing them to dissociate more slowly than the alternate mode. Our results
demonstrate that concurrent binding of multiple anionic lipids by GRP1-PHD contributes to its
membrane affinity, which in turn control its signaling activity.
