Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data

and Computer Simulations

Poster Abstracts

17-POS

Board 17

Coarse-grained Modelling of Conformational Changes in Focal Adhesion Kinase upon

Oligomerization

Csaba Daday

1,2

, Frauke Gräter

1,2

Heidelberg Institute for Theoretical Studies, Heidelberg, Baden-Württemberg, Germany,

Heidelberg University, Heidelberg, Baden-Württemberg, Germany.

Focal adhesion kinase (FAK) is a membrane-bound protein found in focal adhesion sites, the

kinase domain of which is autoinhibited in equilibrium by the so-called FERM domain. It has

been observed experimentally that FAK is recruited by PIP2, a highly negative lipid, and this

binding is accomplished through a basic patch of the protein (four cationic residues).

In previous work, we have shown in conjunction with FRET experiments that small

conformational changes of FAK happen upon binding PIP2[1], although significant mechanical

force as well as the PIP2 binding is also required to activate the kinase domain[2].

In recent experiments (unpublished data) it has also been shown that FAK can form regular

assemblies on PIP2-enriched membranes, with potential effects on its conformation and activity.

We perform large-scale coarse-grained (CG) simulations on 25 copies of FAK on a PIP2-

enriched membranes to observe and further understand FAK clustering. We find spontaneous

FAK oligomerization with implications for FAK's scaffolding function at focal adhesions. Our

data also point to a too strong protein-PIP2 interaction in the MARTINI force field, for which we

suggest a correction.

[1] Zhou J, Bronowska A, Le Coq J, Lietha D, and Gräter F, Biophys J. 108 (2015): 698-705.

[2] Zhou J, Aponte-Santamaría C, Sturm S, Bullerjahn JT, Bronowska A, and Gräter F, PLoS

Comput Biol 11 (2015): e1004593.