Abstract
The pleckstrin homology (PH) domain of general receptor for phosphoionositides 1 (GRP1-PHD) binds specifically to phosphatidylinositol (3,4,5)-triphosphate (PIP3), 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 PIP3 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 PIP3 binding modes on GRP1-PHD, involving PIP3 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 nonequilibrium 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 PIP3, 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 489-499 |
| Number of pages | 11 |
| Journal | Journal of Computational Chemistry |
| Volume | 41 |
| Issue number | 6 |
| DOIs | |
| State | Accepted/In press - Jan 1 2019 |
Fingerprint
Keywords
- anionic lipids
- free energy calculation
- molecular dynamics
- peripheral membrane proteins
- signaling protein
ASJC Scopus subject areas
- Chemistry(all)
- Computational Mathematics
Cite this
Microscopic Characterization of GRP1 PH Domain Interaction with Anionic Membranes. / Pant, Shashank; Tajkhorshid, Emad.
In: Journal of Computational Chemistry, Vol. 41, No. 6, 05.03.2020, p. 489-499.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Microscopic Characterization of GRP1 PH Domain Interaction with Anionic Membranes
AU - Pant, Shashank
AU - Tajkhorshid, Emad
PY - 2019/1/1
Y1 - 2019/1/1
N2 - The pleckstrin homology (PH) domain of general receptor for phosphoionositides 1 (GRP1-PHD) binds specifically to phosphatidylinositol (3,4,5)-triphosphate (PIP3), 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 PIP3 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 PIP3 binding modes on GRP1-PHD, involving PIP3 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 nonequilibrium 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 PIP3, 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.
AB - The pleckstrin homology (PH) domain of general receptor for phosphoionositides 1 (GRP1-PHD) binds specifically to phosphatidylinositol (3,4,5)-triphosphate (PIP3), 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 PIP3 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 PIP3 binding modes on GRP1-PHD, involving PIP3 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 nonequilibrium 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 PIP3, 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.
KW - anionic lipids
KW - free energy calculation
KW - molecular dynamics
KW - peripheral membrane proteins
KW - signaling protein
UR - http://www.scopus.com/inward/record.url?scp=85075450181&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075450181&partnerID=8YFLogxK
U2 - 10.1002/jcc.26109
DO - 10.1002/jcc.26109
M3 - Article
AN - SCOPUS:85075450181
VL - 41
SP - 489
EP - 499
JO - Journal of Computational Chemistry
JF - Journal of Computational Chemistry
SN - 0192-8651
IS - 6
ER -